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

Foreign. Hey everyone. Welcome to the Peter Attia Drive. I'm your host, Peter Attia. 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@peterattiamd.com. 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. 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Again, the podcast will remain free to all, but my hope is that many of you will find enough value in 1 the podcast itself and 2 the additional content, exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest 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 interests, you know, are wide ranging from prevention in 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 in detail and understand who are the ideal candidates versus who is not. All of that, I don't want to say paled in comparison because that would minimize it, but 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. And so we just spend 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 angiograms and things like that that we get asked about all the. 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 touch 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 enjoy this podcast. This is one of those ones where the shownotes are really going to be helpful, especially for people who actually want to go back and look through all of the literature in all 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. Ethan, thanks so much for making time today.

Thank you, Peter. Thanks for coming over. Rainy San Francisco I can't believe this.

Is the first time I've been to your office, which I must say, anyone who knows me knows how much I love whiteboards. But 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. And I love it. Actually, my kids love it too. They've staked out their own territory on this one.

I actually like that the kids have their drawings adjacent to the drawing of mtor.

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 19. 1986 Edmonton Oilers signed by none other than the Great One.

Yeah, look, I grew up in Baltimore, which was not really a hotbed of hockey. I think they were the Skipjack minor league hockey team. AAA team, I guess. I don't know. Do 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, 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 Blackhawks 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 the Edmonton 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 capitalist fan, which was sheer torture until last June, which was super fun. But in the process of being a fan, of course, I always remained 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 flight. 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 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 manning the table stopped me, and he said, hey, buddy, I see you walk by that a few times. Do you have any interest in it? I said, yeah, I've got interest in it, but I can't afford that. And he said, no, listen, I'm pretty sure if you bid the minimum, you'll get it. And the minimum bid was $100. And I said, you got to be careful. 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 Stanley 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 early 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. I just wanted to make sure I never grew out of it. And I probably wore it for, like, 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 at one day.

That one's amazing. So, wait, you grew up in Toronto?

Yeah.

And you were an Oilers fan?

I was. I mean, the Leafs were not. Toronto's such a great hockey town that, you know, going to games was, I mean, just the greatest highlight of my life. And I even got to see a few Oiler games, you know, always in the cheapest seats in the house. Maple Leaf Gardens had, you know, sort of this color system. So the gray is up at the very top is where I usually sat. But back 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, you know, be like, right there, you know, 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, you know, sort of hard to believe that you could have Gretzky, Messier, Curry, Coffey, Kevin Lowe, Grant Fuhrer, all on the ice at one point in time.

It was hard to believe before I went to Edmonton, but I took my daughter 4 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 days in Edmonton in July, and we walked by the old.

Whatever it was, Northlands Coliseum. It was. Yeah.

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 there are great things about it, but it's not glamorous. It's certainly not like la.

Yeah. It's not like that was the New York Rangers. Yeah.

Or even Vancouver.

Or Toronto.

Or Toronto. Or Montreal.

Yeah. 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, so I was born in Ann Arbor, Michigan, where my dad had done his internship. And like a lot of people 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 is I didn't really understand what my dad was doing. I was young, I was only 2, 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 in 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 had. Remains on the faculty there has been, you know, been on the faculty for over, 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, 21 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. I was a pretty bad. I was a very average student in high school, but particularly an average or mediocre science student. And so I went off to college. I went to 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 at 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, 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 ten 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 us humanities people and we were ranked in the class one to 120 and we all ended up in the bottom. We were 110, 111 through 120 and struggled mightily with science, 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 the 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 from the outside you have people. 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 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 I did. 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'd 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. 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, it was sort of like, I guess going to med school at Hopkins in that era was like playing for the Yankees. In the end, I agree with you. After I interviewed there and I made a point to stay an 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 a 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 having grown up in that environment and, you know, 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, you know, of course now I do, but I wouldn't trade that experience. It was an amazing experience. And all those people, I mean, I remember operating, I did as a medical student, I did GI Gold.

That was back when Cameron Yeoh. And 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. Well, I spent a lot of time in the operating room with Dr. Cameron and wow, I mean, what an entertaining human being and master surgeon.

I don't know.

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. As a student, you were terrified because they told you residents would tell you. They're 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. 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.

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. It 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, 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 take a little nap, you wake up, you'd have some dinner, you go back to sleep, you 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 an 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 ocular eight 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. I mean, These were some of the sickest people in the world. This is pre protease inhibitors. So sick, sick, sick 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 CCU 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 summer between first and second year. I worked in a lab. I worked in a neurosciences lab. I was working on the genetics of trinucleotide repeat diseases. So 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 trinucleotide 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, is anybody here doing work on the pathogenesis of. It wasn't called ACS or acute coronary syndrome back then, but the pathogenesis of unstable angina or am I in 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. And he had an illustrious academic career. His name was Pascal Goldschmidt. 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 and 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. I'm not entirely convinced I know the answer yet. But I 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 myocardial infarctions. 99% of heart attacks in this country happened because of a ruptured atherosclerotic plaque. So.

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 angiogram, 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 did autopsies on people who presented with sudden cardiac death. So somebody would show up dead from a heart attack, they do an autopsy, 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, proved 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 first demonstration that this clot event was the primary cause of most heart attacks. 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 it was. I'll have to go back and find it for you. But he described something that stuck with me, which was that if you look at an autopsy, somebody who presents with a, you know, with a heart attack and dies, you'll find you can tell by looking at the histology how many times the plaque has actually ruptured, 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 Varami and others have said that a lot of the progression of coronary disease, so getting narrower and narrower is probably that event happening sequentially. So plaque rupture, healing, and then as you do that, you're laying down more fibrous 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 paths in the same plaque. So in the same plaque. And so that told.

So basically a seven ringed tree. On the COVID of Staari'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 COVID 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 none of 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 endothelium, which is that inner lying of our blood vessel and that's there to sense injury. And when the blood sees tissue factor, the blood, there's a biochemical reaction that we've been described for 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. 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, I think 1988 that ISIS 2 was published and ISIS 2 was the. This is off 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.

Tell folks what streptokinase does.

So streptokinase is a, what's called a thrombolytic. So streptokinase is a natural substance that we make, or we make something similar that dissolves clots. So clotting 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 injury 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 through 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. 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 coagulant coagulation factors, say any of the 1 factor 2, Prothrombin, you'll get a sick mouse, but the mouse will survive through development. So they will survive. And then what kills them is the process of being born. So they'll die right after birth if you knock out one of the anticoagulants. So knock out, say, protein C, protein, protein S, any of the anticoagulant. 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 layer which we won't have time to get into today, which is the role of the placenta and how placentas don't clot off. And there's just unbelievable, fascinating evolutionary biology that we can do.

Unless someone has HELP syndrome that becomes this awful exception to that rule where you get these infarcted, clotted placentas, and then the fetus is usually underdeveloped.

Well, now, I'm 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 and again, is an undiagnosed hypercoagulable state, I think, because basically the placenta ends up clotting off. Yeah.

You're saying in the case where you don't have an obvious aneuploidy or a chromosomal abnormality. Yeah. 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. You got sidetracked.

Yeah, that's what I do here. I sidetracked.

That's all right. That's fun. So myocardial infarction was defined clinically as most things were and 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 electrocardiogram 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 a. Every time the heart beats, there's a signature that can be measured electronically. When you put leads on the chest and you have a little wave that symbolizes when the atrium is doing its contraction, that's called the P wave. Then you have the big signal, which is this QRS spike, and that's this ventricular contraction. And then you have another little wave called a T wave. And I can't even remember. Is that the repolarization?

Yeah, 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 distal to that clot. So beyond the clot. So then any tissue beyond that blockage would then be starved of oxygen, and after some period of time, a few minutes, five minutes, would die. And wasn't that long ago 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 pharmacological bed rest and then aspirin and then streptokinase, 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 stents. But the nomenclature at the time that I was a medical student was you defined myocardial infarction, so mi, by the presence or absence of the Q wave. So 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. So 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 myocardial infarction. And what that meant was that there was transmural all the way through cell death. So the entire wall there had been an actual necrotic, basically had become necrotic and died. Whereas there was another version of heart attack at that time that we called non Q 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 creatine kinase, and that's an enzyme that's leaked out of the cytosol 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 have chest pain, but they didn't have this Q wave. And so they were called non Q wave myocardial infarctions.

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 in 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 that gets done when somebody shows up. They're 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. And unstable angina was thought to be the same pathophysiology, so ruptured plaque, but it was thought to be incomplete cessation of blood. So maybe the clot didn't completely block the arteries. There was 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 rise in the biomarker, you were said to have unstable angina.

And that was differentiated from stable angina based on what?

Yeah, 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 intolerance to actually that feeling of 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 symptoms. 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 angina, and still mostly called stable angina, 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 increase demand. Sometimes people call it demand ischemia. And so the idea was that if you have this blockage that's 75, 80% 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 nitroglycerin 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. You can dilate the distal segment after, but you can't really deliver more. And 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 coronary steel. So, in other words, you're getting more blood is even being taken away. And so that syndrome is considered to be stable angina. So you're walking up a hill, you get chest pain, shortness of breath, whatever the symptom is, you sit down and you rest, and it goes away. Or like you mentioned, you take a nitroglycerin 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 not 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 morphologically, 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 chronicity of the problem, the fact that people talk about how stable angina doesn't typically kill people. It develops slowly over time, months or years. There can be an 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 at rest 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 I'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 50%. 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 happen in this series of people who came in and died happened in arteries that had only 30 or 40%.

I think that's actually correct. And 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% 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, right, 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, you know, someone who's walking around with a 95% stenosis is very likely to. 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 there are obviously 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, 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 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, but 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 Q wave, non Q wave. Talk to me about what is nomenclature today.

This nomenclature evolved over the past 15 or 20 years. And the reason it did was that 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 Q wave 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. At 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 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 signaled that there was a complete blockage of an artery. And that then evolved into 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 Roundwald and other people in the Timmy group. And it was done with a combination of pharmacology, so streptokinase, 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 Q wave and the ST elevation MI are probably the same. It's just you're seeing a later manifestation of the Q wave. 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 ST elevations. They probably just missed it. So they saw the Q wave because that was what came later. The non QA of MI is probably now what we call non ST elevation mi, and it's actually evolved to a different term, which is I don't love, which is called non ST elevation acute coronary syndrome, which is just not as.

Easy to say as non stemi.

No, no. So acute coronary syndrome, I think the way I teach the students is acute coronary syndrome is the entire collection. It's everything and includes STEMI's, non STEMI's everything, and it includes what we used to call unstable angina. Unstable angina 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. I'm not an electrophysiologist, 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 ST elevation, it triggers 911, activate the cath lab. This patient goes straight in. They get heparin, they get aspirin, they get all the other things, clopidogrel.

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. And this change happened during the time I was a cardiology fellow. So when I was a cardiology fellow, somebody showed up in the emergency department with ST elevation. 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 cath lab. But since Gene Brownwell coined this term time as myocardium, since we understand that the longer that the heart is deprived of oxygen, the less chance it's going to actually recover, there's been a push to speed things up. And so now there's.

So 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 interventional cardiology team and 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 stemi.

You hear about it when they're in the cath lab?

I hear about it.

Or maybe 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? In the old days wasn't that long ago, 15 years ago, this cardiology fellow 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 savings potentially?

Maybe. Maybe. I mean, every hospital now in this country, country is measuring their, what's called door to balloon time or door to open artery time. It's a quality metric. And like every quality metric, there are 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 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 biggest overall net net, I think our society of people, citizens and cardiologists and other people and emergency room doctors, I think all agree that this is better than it used to be. The dilly dallying that would happen and 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. It's a little bit of radiation.

So which trial 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 STEMI patients is going to save lives?

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 done 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 going to 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 femoral artery. So the femoral artery is a major offshoot of the aorta, feeds your leg.

Oxygen, you go into the crease in the groin and anybody can feel their pulse there. So if you feel that that's your femoral artery, that's about the size of your, 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 called the modified Celgener 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 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 coronary catheter, which I think is like 2 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 aorta 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 osteo are. So in normal human beings, there's a left coronary osteom and a right coronary osteum. And you can put that catheter and engage it. And then that allows you to inject contrast dye, which under X rays will allow you to actually see the artery or see at least the inverse of what the artery looks like. And then what people realized 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 re. Establish 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 put. 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 dam there, and you just take a bulldozer or you take a shovel and just shove all of it downstream. And so one of the questions I've always asked is, well, why is this therapy not more effective? And we'll get into where it's effective and not effective. But is there potentially a downside to elaborating all 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 this stuff that you elaborate downstream when you're blowing open this artery? And actually goes back to the question of sort of when people were doing these trials to compare the efficacy of what's called primary angioplasty versus thrombolytics, TPA or streptokinase, these chemical drugs.

So the mechanical versus the chemical.

That's right, yeah. 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 subdural 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 a 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, were 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 this 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 showed up with a heart attack at San Francisco General Hospital. That's not the case anymore. I think 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, they said, God, Doc, I'm walking up the hill and I get this burning in my chest and I sit down and it goes away. And 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 that 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, in people with stable angina, a certain percentage of them, probably 40, 50, 60% of people would show up with what was called restenosis. And restenosis 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 leave this metal scaffold behind, you can actually improve the likelihood that it's not going to reach the nose. So, so stents completely cured the physical recoil problem, which I think 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 stent, you created a lot of injury on the vessel wall. And so the body's reaction to 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 fibrous scar tissue inside the stent. So before the era of what are now called drug eluting stents, this is back in the 1990s, if you did a stent on somebody, again, stable angina, you'd see that there was 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 ischemia. 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 restenosis. We went through this entire period of five or seven years of trying to find ways to solve restenosis, including radiating the inside of the vessel wall. But when I was a cardiology fellow, 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 were going to make the scar tissue. And God knows what we were doing to each other and to the patients. But that went away in the early 2000s with the advent of what are called drug eluting stents. And we can talk about those. But you probably already talked about them a bunch.

Well, no, no, actually 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 eluting 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 at Columbia named Andy Marks. I think he actually figured this stuff out. But we'll 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 use to treat cancer. And so again what I described in a simple way that I think about it is that it's a proliferation problem. So 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 fibroblasts 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 restenosis for the most part. Now that problem is no longer.

And there was a bit of a hiccup in 050607 when the drug eluting 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 Boston Scientific inhabit 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 that 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 all these other things. And so it was a, as a general cardiology fellow and somebody who was interested in basic science, I wasn't paying attention to the nitty gritty 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 loading stents was so if you back up to the early 1990s when stents first started getting used in coronaries, one of the biggest problems that happened was that you'd put the stent in there and Then within a period of a few weeks, a non trivial amount of people would come back with effectively was a stemi, the stent 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 downstream tissue factor. But people couldn't use these stents for a while. And then in 1996, and 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 New England Journal of Medicine and that same issue, so our paper 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 Tyclid. And so Ticlib was the first generation of these, what we call thionipyridines. Thienopyridines act to block. At the time we didn't know this, 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 interventional cardiology, is if you gave people this drug titlid at the time they got their stent, the chance of the stent clotting off went to almost zero. And eventually that drug had some toxicity and was replaced with the drug that's used in most cases still today, called clopidogrel, which is acting on the same receptor. It's the same biology.

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, 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 stemi 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 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 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 we're in the drug eluting stent era and we've solved the restenosis problem. But people are showing up now. They've taken their plavics 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 stemi 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 prothrombotic, so they probably trigger some clotting. So what we realized was that people, your own body would basically wall off 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, atherosclerosis 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 will do that, to high blood pressure will do that. You have to have a lipoprotein that can actually carry cholesterol through that injury. So you have that injury, you can get it right 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 stent will re endothelialize the inside of the stent within three weeks, four weeks. The standard of care in 2002, 2003. But before drug loading stents was take Plavix for one month and you're done. And people did great. And then drug loading stents come along, they solve this one problem, but they create a new problem. The problem was that in addition to inhibiting the proliferation of these smooth muscle cells and fiber blood inhibit the endothelial. Exactly. So people were ended up coming back with this stent thrombosis problem. Now, months later, then it became unclear about what the correct amount of time to take your Plavix or other drug was after a stent. And I think now there's some great work being done by people. I think for the most part with these newest generation drug eluting stents that have the, the right mixture and cocktail of drug on them and they're really easy to deliver and cause 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, whatever it is, few months, all that matters is your Plavix. 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 show up in the hospital with stent thrombosis, it was often because they hadn't been told appropriately strongly enough that they had to take Plavix.

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 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 clinic, says, you know, Dr. Weiscott, 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, 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, lo 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 going to say cardiology. So in the 1980s, that patient gets a prescription for nitroglycerin and beta blockers. So beta blocker help 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 going to be less likely to get symptoms. And nitroglycerin, as we 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 bypass because there was no other option for what we now call revascularization. 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 won't have 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 Mammary 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 you're. They're beautiful blood sources, and you just attach it what we call distally so past the lesion. And by the way, if my memory is correct, it was only Lima to lad. It wasn't Lima to circ. It wasn't Rhema to right main. 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 Aldine. It was only a subset. Right. So I think it was. You had to have multivesal disease, left ventricular dysfunction, diabetes. I mean, there were a subset of people. 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 sternotomies, which, when you think about that, I mean, imagine signing that consent form.

Golly.

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 ladder, effectively bypassing this thing, works, at least in a subset of patients, shouldn't we be able to roto 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 revascularizing 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 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 cause mortality benefit, doesn't mean that there's not benefits. So I think that the advent of the stent era was remarkable. It happened to coincide with the advent of the statin error. Right. So the first statin, lovastatin, was approved in 1988, I believe. So remember I had said that we were treating people with angina with 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.

So let's back up and just make sure we re emphasize, because I don't think this point cannot be emphasized. Emphasized too many times. So if you show up in the hospital or in the emergency room or anywhere in the world with this 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 do not pass go, do not collect $200, you're going straight to the cath lab.

That's right. If you show up and you have a non stemi. So chest pain, let's say you have positive biomarker. So now, modern day we use another biomarker called troponin, which is just a component of the architecture that allows muscles to contract and there's an isoform of 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 troponin and an EKG change that is not ST elevation. Anything other than ST elevation 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.

Now let me ask you a question and we didn't distinguish this, but it's worth adding. In the STEMI 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 stemi, 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 stemi, so hemodynamic instability, meaning your blood pressure is very low or you have heart failure, you have fluid in your lungs, something else that makes it complicated or you can't treat people, can't make their chest pain go away with medicine and 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. Well, it may not be within 60 minutes, but it'll be quickly again, depending on how complicated. If you have uncomplicated non stemi, 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 cath lab and they would get a stent 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 clear mortality benefit by opening up the artery Again, if you're in Uganda and you don't have a cath lab, then TPA is the best you can do. But opening the artery saves lives. In the non stemi situation, if you're hemodynamically unstable, again, same thing. Opening the artery saves lives. If you're hemodynamically stable, 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 interventional 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.

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 of is there, in addition to a symptom, relief that you'd get from putting a stent in an artery of somebody who's got a blocked artery and has stable angina?

By the way, I'm just gonna interject. 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 sorry. 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? Gives you the bottom line and then it tells you what it stands for. Okay, so mage points. So it's called Clinical Outcomes Utilizing Revascularation, an Aggressive Drug Evaluation. Parenthesis, 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 on the Runway and it's taken a while to take off, I'll just open it up and search by subjects. Like, I wonder 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. I will be intentionally less detailed about how I describe these trials since 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 hard 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, are 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. And this is something I'll have to go back and look at, but I believe the people randomized to the interventional 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 in heart outcomes by stenting, that this we were going to prove finally that opening the arteries did more than just relieve symptoms. And it was negative, 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 even.

I remember that 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, God, if 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. You'd show up there with, like, too much farting or something, and then he'd do a calcium scan on you, and you'd see a calcium score of 20, and he'd say, we got to take you to the cath lab, and then he'd put stents in you. And there was really no way to argue against that, even in asymptomatic people. It was just a crazy time. So this definitely was a big result in cardiology, particularly in 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 to date. So you could say the burden of proof, the onus is on the interventional 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. Doesn't mean that it's not important. 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 angina patients.

So then what was the impetus for Orbita ten years later?

Well, you would have to ask Daryl, and I hope someday you could ask him because he's a phenomenally entertaining guy.

Yeah, you got me onto him and his work, and I follow him on Twitter now, and I think he's in the UK and I can't wait to hopefully meet him at some point.

He made this tremendous appearance and splash on Twitter a year and a half ago and set the world on fire because he was fearless and obnoxious and just everything you 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, courage kind of established that there's not going to be a benefit in terms of heart outcomes. So we've sort of settled on this idea that stents are there, and they're useful for treating symptoms in patients who fail medical therapy. But Orbita was. Are stents 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, interventional 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 investigation, 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?

Stuff.

So anyway, the key differentiator of this trial is 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 the, not obviously the interventional 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 cath lab, they'd put a catheter in your leg, they'd wind a catheter up into your coronary ostium, 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. 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 size 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 argued 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, sort of, 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 didamine stress test. So 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 misspeak and piss off all my interventional friends, but for the most part, they. 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 stents. Not only do they not reduce your risk of having a heart attack or dying, 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 stent placed after what I don't believe was a stemi.

That's right, he had stable angina. 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'd go and stent 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. What 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 tomorrow. But I say what I convey to you today is that while stents may or may not be useful in some circumstances at reducing your symptoms, if you have bad symptoms, it's very unlikely that in stable angina 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 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 stents, 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 that we do and don't understand. So what I say is, look, our 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. But for the most part, I'm sending the same number of people, I'm sending the same people to the cath lab as I did before Orbita.

Yeah, it's probably just the composition of those patients is probably migrating constantly. And that's. I think 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 in my lab, in our lab, that if you know the answer to the experiment before you do them, we don't need to experiment. Just stop. We can write it up, right? What are we going to 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 0.05 means that there's a. 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. And 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 it when something defies my expectations.

I don't know that I can say I enjoy it 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 in a CT angiogram is. But so just give us 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 trying to optimize to the best of my extent, my ability versus whether that maybe the best thing I can do is leave you alone. And you've probably seen examples too where, I mean, I remember again, as a cardiology fellow, 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, everything, and the patient got better because they were just over managed. 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, occult 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, am I going to die of a heart attack and what's my risk of dying from a heart attack? Or 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 in trying to understand it. But a lot of these tests we'll talk about, I think 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, that we just 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 and even part of the process of getting from here to here, point A to point.

B. 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. 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 described, 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 to 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 one's 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.

Right.

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 want to get your product to market, whether that product is a stent or a drug or whatever it is. And the best way to do that economically is the shortest amount of time. And so you want to take the sickest people. So these trials, I mean, I joke that like a prevention trial, the kinds of trials that I want to do would take 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'm 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 patience, that we're going to be wrong. There are a litany of examples like LP was something I didn't pay attention to until the past few years. Coronary calcium scan. If somebody came to see me with a coronary calcium scan 10 years ago, I would say I wish I didn't have this information, but I never ordered one before seven to eight years ago. So there are lots of examples of things that I didn't used to do that I've now incorporated into my practice. And I'm doing so without that safety belt of evidence basis that we're used to. There's not going to be a orbital like 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 again this year. Just doesn't happen.

That's a great way to explain it.

Whereas the other way around, I've had a few patients, but as if you're.

An orthopedic surgeon, for example, you break your leg, you fix it, or an.

Interventional cardiologist, right, you show up in the cath lab with a stemi, 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, and I've been public about them on Twitter, that are treatment failures, but maybe not personal failures. In fact, I don't think I managed 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've 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 insistent 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, and it's 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 there are physiologic tests. So physiologic test 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, determine whether there's ischemia, meaning there's a difference in the supply and demand of oxygen. So you can use EKG or 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 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 angiography. No symptoms, just I want to have an angiogram. I want to know that I don't have any.

Right. Just a preventative. 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 angiography 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, are they are triggers for basically saying yes or no to statins, or yes or no to statins and PCSK inhibitors, or 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 it'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 100 years 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 radio opaque. So people realize 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, 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 0, 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 her.

It gives you absolutely no additional risk. Stratification. Conversely, when a 90 year old shows up and has a calcium score of zero, it's quite informative.

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 1%. 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, your depressants are absorption.

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 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 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 informative.

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. I frame this as I started off thinking there was no value to calcium scans. I evolved to think, all right, well, there's going to be value in these two quadrants you 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. Asymptomatic primary prevention.

I have a 49 year old who just scored 4500.

I mean, that to me is useful. So that takes us again, not going to 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 want to be even more aggressive. And so that's when you start thinking this is actually going to change what we do or change, at least in my head, the risk benefit ratio anecdotally.

I want to tell you about that patient because this is just getting off in the weeds a little bit. This is a patient whose family history, if I shared it with you, you would say, oh, he's going to have an elevated LP. Father had first MI at 42, dead by 49, brother had MI in 40s, et cetera, et cetera. When you hear these stories, you say, well, it's elevated LP for sure. You do an advanced blood test on him, normal lp. And you want to 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'Re the so called widowmaker.

You look at this thing, 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 lipids. He had no obvious risk factors. And then we got his LPA back and it was high and I was released 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 Tamikis ASOs are around. Did you look at his aortic valve yet?

It's normal.

It is?

Yeah.

That's so interesting. I would have guessed someone that young with such aggressive athera 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 year olds would clearly be 5 to 10% still. So that's another thing that I just find very sloppy and I don't have these discussions too much in social media because I find it so frustrating, but it's that you just don't 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.

So MESA Multi Ethnic Study of Atherosclerosis, one of the two largest cohorts we have ever to study atherosclerosis along with Framingham.

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 the calcium. And that's somewhat helpful. But again, it comes back to this being way more art than science. I Mean, this is at this point in primary 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 angiograms basically said, look, we're going to do more or less what the angiogram 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, if 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 IVUs. So IVIs is intravascular 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 on the surface.

That's right. Luminal 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 lumen more than a couple percent, if at all. It may just look like a normal variation in sort of lumpy bumpiness. But you'll see plaque. 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?

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 angiogram 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 you feel a bit more comfortable that your level of aggression can be lower. And the converse then is true as well.

So then what's the cost? Right. So other than the theoretical cost of the radiation, which is probably something.

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. At about 2 millisieverts of radiation. So for the listener, millisievert is the unit in which we measure radiation. The NRC limits people, or suggests an upper limit of 50 millisieverts for a year. We want our patients to be below 20 millisieverts for a year. Living at sea level exposes you to maybe 1 millisievert over the course of a year. Living in Denver probably exposes you to 4 or 5 millisieverts for a year. So that puts the 2 millisieverts in context. The first generations of these. Ethan, 20 millisieverts just for a CT angiogram.

What's a chest X ray?

Incredibly low. It's less than 1 millisievert.

So we can sort of dismiss that. There's very little risk of the contrast in most people. Obviously, if you're older, you have kidney disease, something else, then it becomes a different issue.

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 2000, $2500. So it's a quite expensive study relative to the CT, the calcium score, which I gotta put a plug in, by the way. Your institution here needs to get its head out of its ass.

I mean, Jesus, I send patients to Stanford.

Stanford. Stanford's doing CT angiograms for like, 100 bucks. And you coconuts here are charging, like, thousands of dollars.

Don't get me started. Well, I think it'll change now with the new guidelines. I think the price has to come down. But it's such an interesting.

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, of there 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 going to get it, no one's going to 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, 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 going to 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 the hell out of me, I don't want cancer anymore. Get it out. And even though prostate cancer is a great example, there are lots of ways to treat prostate cancer, 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, I can't dissuade them of that. That to me is the one. Cause that's where I would you 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 in 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 in about the past. 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 CT angiogram. 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 want to use heart flow in. So I don't want to 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 that 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 intravascular ultrasound IVUs. And then the other one was this FFR, which is a way of measuring pressure and basically inferring the degree of blockage that way.

So 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. 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. In a normal artery, you'll see it augment. In a diseased artery doesn't. It'll go 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 2. I'll spare everybody me looking up exactly what Fame's 2 stood for. Again, what did those studies show?

The take home. And again, there's controversy. As with almost anything in cardiology, there's controversy, but the take home was that if you had an FFR that was less than 0.8, so you use a mathematical formula to basically calculate. And if it was less than 0.8, if you then put a stent in that artery, people did better. So it suggested that this could be a useful tool to help stratify who should be getting stents and who shouldn't be getting stents. And I think a lot of our interventional cardiology colleagues have been, been using it that way for the past few years. Again, there are questions, I don't want to get into the controversy, but 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 infer the pressure using Ohm's law. So they did the same thing. They gave it vasodilator not. And they can do this.

Boyle's law.

Sorry, Boyle's. Yeah, yeah. I don't know, you're the engineer too.

It's been a while.

So they did this and lo and behold, they were able to measure this thing non invasively. You don't have to have a catheterization, you can do it all through ct. And then Heartflow basically is selling this software as an add on package to the CTA and they'll give you, give you what's called a ctffr, which is their like calculated ffr.

Is this changing your practice? Because I've, you know, 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 in 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. 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've ordered one. I've ordered a lot. So I reserve 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 going to be a huge game changer because what information is it adding and. And how are we going to 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 value is it going to bring to you or 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 cath lab 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 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, Luke Hantley. I mean, we've got insulin receptors, pi3k, we've got mtor. You've even delineated between mtor complex 1, two pathways to autophagy, lots of 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 of the person who became my mentor, was my boss until he left to go work at Novartis a couple years ago. A year ago, Two years ago. Sean Coughlin 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 dumb. And so at that time, I got very interested in the biology of sex differences. And. 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 placenta and pregnancy. Men don't have to have this other thing living inside of them, and therefore could afford maybe to optimize more towards a 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 it 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. 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 evolved to be the less sort of 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. And so they're a little bit more susceptible to bleeding. And there's the added 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, well, it must be sex hormones, and did some early kind of pilot studies looking at the role of estrogen, estrogen 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. Of a mammal, human or a mouse, there's a set of genes that are expressed dramatically different, even up to 100 fold different in males and females. And a lot of these genes are genes that regulate sex hormone, sex hormone binding 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 chip array or 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 are clotting factors made the liver. So I thought well this is what we're going to do. And so I set off to basically try and understand how this happens. So what regulates the dimorphism of liver gene expression in mammals? Turns out it's not sex hormones that's actually secondary. It turns out that it's a, 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. If you 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 in Cell 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' 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 is 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 hormones and you can completely reverse the signature of their gene expression in the liver. And you can do the opposite with a female mouse. Take a female mouse and because if you give exogenous growth hormone you basically suppress endogenous growth hormone secretion from the pituitary. You can give a couple of injections, I think it's just one or two a day to a female mouse and you masculinize the liver.

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 Nir Barzilai on our podcast, and I would say that Nir'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.

Okay.

Oh, yeah, yeah, we did that experiment. So I got into this because I was interested in clotting, and that makes sense. As a cardiologist. We just spent two hours talking about why clotting is 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 clotting, get into this growth hormone pattern. And so we started to do that. And we, as a lot of people of my generation do, science is a little bit of a game of you do what everyone else does and see what 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 JAK2, 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 hormones. So downstream of the receptor growth hormone binds, JAK2 basically allows this signal to be transduced.

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 cytokine receptor, doesn't have any intrinsic tyrosine kinase activity. It has to partner with this other non receptor tyrosine kinase, JAK2, to transduce the signal. So we eventually knocked out JAK2 in the liver in hepatocytes. And I'll never forget that I had a technician working in the lab at the time. 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 JAK2 and hepatocytes were basically turned into adipose tissue. It was the most.

You were creating nafld?

Yes.

So just let me make sure I understand what you're saying. If you knock out JAK2 in a liver, you prevent growth hormone from exerting its transduction in the liver because you need jak2 as that second tyrosine kinase. So it's basically like taking away growth hormone from the liver.

That's right.

And if you do that, you accumulate fat in the liver 25 fold. Increase in 25 fold. So it becomes clinically grotesque. I mean, you just basically create foie grasp.

In fact, there was a moment in time where I thought, well, this would be a fun side business. I'll just make foie gras because we can engineer it.

Quick question. Did the triglycerides go up or stay the same serum? Yes.

No, they were the same.

So in other words, you shut off export, it seems like, significantly. Right. There was no flux, there's no outward. You were basically not getting any VLDL or triglyceride out of those livers.

Well, so we didn't know what we did at the beginning. We had no idea. In fact, I didn't. I took the liver to a pathologist because I said, 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 nafld. And I said, what's nafld? And he said, it's non alcoholic fatty liver. And I said, okay. And so then of course, like, I started with the very basic, like, all right, well, what are the causes of nafld? It's an increase in synthesis or increase in dnl. It's a 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 we published a model that I think mostly we've 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 hepatocyte and other cells is this protein called IGF1, insulin, like growth factor 1. And 95% of circulating, if not more of circulating IGF1 in the plasma. So if you take blood of you or me comes 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 in cells and tissues, but circulating IGF1 goes to zero. And circulating IGF1 is the plasma biosensor for growth hormone. So growth hormone's half life is extremely short. So we evolved a 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 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, dude, 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 does as a plasma biosensor for 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 hepatocyte. So you probably remember the growth hormone has been described for a long time, forever and ever to be pro lipolytic. So it's actually one of two hormones that's both catabolic and anabolic. But it turns on. It's a way to mobilize fat from adipose tissue stores.

Testosterone being the other where you can be anabolic to muscle, catabolic to fatigue.

That and thyroid hormone, I think, is another one where you can be both.

Unlike insulin, for example, which would be Anabolic to both, or cortisol, which would be. Actually, cortisol is the reverse. It's catabolic to muscle, anabolic to fat.

That's right. So in any case, if you give an animal growth hormone, if you have a patient who has a tumor, that secretes growth hormone disease called acromegaly or gigantism. Right. Andre 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 that growth hormone was turning on lipolysis and mobilizing all this fat and that that fat was getting taken up by the liver. What was interesting was we did a relatively deep analysis of sort of all the mouse models that have been made involving the receptor GHR downstream signaling components, including JAK2 and another one called STAT5. And we looked at animals that had 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 one to two fold increase in lipid in their liver, very modest, if hardly noticeable. Whereas if you knock out the receptor or this other molecule, STAT5 or JAK2 selectively, just in hepatocytes, you get this 20 to 25 fold increase. And 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, we did what people do, which is we did a gene expression array. We saw there's a molecule called CD36, which is also known as fatty acid translocase. And we saw that it was increased by 20 fold in these animals where we knocked out JAK2 in the liver. And we thought, well, gosh, this could be facilitating uptake. And so we did, did a series of follow on experiments after that where we knocked out CD36 just in hepatocytes and showed that we could make that get better. So we put together this model where growth hormone, basically growth hormone secretion is disinhibited at the level of the hypothalamus pituitary. 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 upregulation of this molecule.

Now, if you block JAK2 and block. Block the expression of CD30E6. Do you eliminate the fat accumulation in the liver?

Yeah, that's the experiment we did. It wasn't 100%, but we basically brought it back down to almost. Instead of it being 100 grams per milligram of tissue or something, it was 20, where normal mouse 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 adipocytes, since we're presuming that this must be a product of lipolysis? So what happens if we block this pathway in adipocytes? So we went and made an animal where we knocked out JAK2 in adipocytes selectively, and then we crossed the tube 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 what was so fascinating about that experiment was we never intended to get into any of the insulin glucose homeostasis stuff at all. But when you're doing these experiments, they're expensive. And so we did a bunch of things. I think we did an insulin tolerance test for some reason on these mice. And we saw that the mice where we knocked out JAK2 just in the adipocytes, had the most profound insulin sensitivity. 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 and 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 knocked out this pathway just in adipocytes, and we saw that if you knock out the pathway in.

Adipocytes, but I'm confused. So you knock out the pathway in adipocytes 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 wanted to then put it into fat. Into the fat cell, right?

Yeah. And what you're asking is a phenomenal question. And we had initially, I think, naively thought that this was an adipocyte autonomous effect that we thought must be the adipocyte, but then there's not that much glucose that's actually disposed into the adipocyte on a per mass basis. So 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 masquerades as profound insulin sensitivity. But you basically clamp the portal vein, metaphorically, and you kill an organism in five minutes if you stop hepatic glucose output. How quickly did you see these animals die?

It was within 30 minutes.

Oh my God.

It was really profound. And so this then sent us off in this long, what's now been a 10 year journey to try and understand how growth hormone regulates insulin sensitivity or insulin glucose homeostasis and how that happens through the adipocyte. 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'm surprised. This guy, Bernardo Husai, who's an Argentinian 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. It was the most unbelievably productive period of time I've ever seen. And he ended up winning the Nobel Prize. He shared the Nobel Prize with the Corey's of the Cory cycle, which, 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 set of experiments 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 the toxic effects of insulin so that they bottomed their blood sugar out. He then did the opposite experiment where he took an animal, he lopped out the pancreas and then saw that if he got rid of the pituitary gland, that they were less susceptible to the hyperglycemia, that they basically had improved diabetes. And 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. And in fact, there were people in the 60s, I believe, who were doing hypophysectomies in people with very brittle type 2 diabetes.

So severing the link between the hypothalamus and the pituitary.

They were taking the pituitary out.

They were taking the pituitary right out. Wow.

And it was a very effective treatment, actually, except that it had 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 1983ish or so. And 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 stopped the GH injections and it could 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 Somavert or Pegvisimon. It's a analog of native wild type. GH 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 paper they actually talked about growth hormone secretion being as much the cause of brittle type 2 diabetes as has 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 teleos. So there's no growth hormone in flies or worms, it's only in invertebrates and teleosts. 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 hormones 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 hormone's acting as a brake 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 to. You didn't mention IGF binding proteins, but where do they fit into this? The IGF BPs 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 nadir 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 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 or in acromegaly, is one of the most potent ways to die. Right. I mean, people with acromegaly, untreated acromegaly die in their 30s and 20s and they die of cardiovascular disease. So I think that's gain of function. And again in the animals, 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 yield shortened lifespan. And then the flip side, so you mentioned Laron 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. Right. So they have this body composition where they have a 50% body fat, which you'd think would be dangerous. It turns out that they and the mice. So there's a mouse model of Laron syndrome and that's actually the long 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 Methuselah Prize. And 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 Bartke in southern Illinois engineered the mouse that's missing. Actually, he and John Kopchick did it together, this experiment where they engineered the mouse that's missing GHR. And that mouse lived to be 18, 19 days, which is basically the equivalent of like 200 human years, still to this day, the longest living mouse that's ever been made.

And that meant it was without GHR in the liver anywhere. Anywhere, anywhere. And that means for its entire life, the whole life.

So these are short and fat mice, and they live forever. So. 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 pretty fat. What's interesting is that that fat.

Are they cognitively the same, the mice or the people? The mice. Well, I guess both. But I was asking specifically about the mice.

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 path halfway in the adipose tissue, which is acting at a distance mostly on the liver.

So what do you think confers the protection to the Laurens 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 sensitivity. A decrease in insulin and decrease in IGF1. I can't get better than that right now. But I think the circulating insulin levels are nearly undetectable. And my insulin labs 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 Virta 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, right? 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 Macrovascular disease, atherosclerosis, coronary artery disease throughout the body, obviously 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 foibles 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 foie gras. 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 Laurent 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, right?

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 15% in their age matched relatives. What I heard was that they were depressed and had an increased risk of alcoholism because they were Basically ostracized for being fat dwarfs, basically. I hate to be harsh, but I think that was.

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, inbred 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 in 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 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. And while I'm firmly in the camp and will ever expect to remain in the camp, that lipids are fundamental and probably the most important driver of cardiovascular disease, of atherosclerotic 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 1 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 in 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 Barry Bonds at 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 the data. I don't feel confident. 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, it'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 and 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 going to increase your lifespan, it may more likely even decrease it, but you like how it makes you feel and look, 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 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, it's a Great trial. What happens to your IGF one when you fast?

Oh, it 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 3 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 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, 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 peri fasting 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 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 have you ever. Measuring growth hormone is one of the hardest things to do because it's so.

I've never measured it for that reason. I just.

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 brother Daws 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 one of the things that we're really interested in understanding in the future is understanding its role in this fasting, feeding transition. It goes up in fasting, but as you say, IGF1 levels go down, so you get this selective GH resistance in the liver at least. The question is Whether you're getting GH resistance in other tissues diseases 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 is skyrocketing.

Then the question we should know this and eventually we will what is GH activity in adipocytes? 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 get back to stuff. 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, certainly 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 am 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? What can we do to make science as exciting as it can possibly be? And if for no other reason, I even say this to people, 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. I don't think this fact is. Fact is necessarily correct today, but it was at the time, you know, 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 1% 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 I think, 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.

Depth.

It may be that a lot of the conversation that we had around the science was over the head of the average layperson who hasn't had science. But I still think it's valuable. And they're going to go off and get literate 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 Vale 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 with Dave Sabatini, a series on mtor.

Yeah, I saw that one.

Yeah. If we're going to. To get more people interested in science, we 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. Making the decision as a sophomore in college, that's almost impossible to believe that that could happen today. I mean it could happen, but 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 get into science at a young age, get burned out and don't like it by the time they get to be a fellow or a resident or attending. And the second thing is the people who don't get into science like me, the Ethan Weisses 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 going to 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 three year experiences in the lab. So the kind of thing that used to happen routinely where people would go and work at NIH 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 science scientific literacy, 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.

I mean it's gone now. So you know, I've heard this saying, I don't know who this one gets attributed to, but the gist of it is that we've taken the science out of medical school and the medicine out of graduate school. Right? So our graduate students are craving more understanding of physiology and 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 a 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 dogma. 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, was greater than it is I'm jealous of people like my MD, PhD, friends from Hopkins, like Dave Sabatin, 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 when 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. And, oh, by the way, you also have a family. You decided, like. I mean, I feel like you did it in a week. Cause 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 prototype. You started a company last year.

Yeah.

So can you tell us a little bit about that? Because half my patients now are using this device.

We could do an entire podcast on this one. Maybe I'll.

Maybe we should.

I'll have a podcast and bring you on because I do think there's some of this stuff, like when I first called you, I remember calling you. It was a. Like Saturday or Sunday. And you were generous to take the time to help me think about this. And 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 VIRTA Advisory Board. And I think, to me, it's the most interesting part of this whole obesity story is that 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, 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. 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 8 pounds in a month. It's a 4 kilogram average fluctuation in water weight. So can you imagine if a woman says I want to lose 10 pounds and she's using her scale? It's just impossible.

And you can build in 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 Virta 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 think I still joke about this. In fact, I think I've joked about it with Sami 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 was no kind of carbohydrate to be found on the table. I thought this is a cult, this is weird. And I never really had any curiosity about doing it. 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 week, is it allows you to follow biomarker. And that if you use that biomarker 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, as 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 and 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 Virta. So Virta is successful at what they do in a different population. 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 this 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 mean, I feel like I had a prototype in October because I manage my calendar through my fasts, which are always beating. And then of course by December had the version I have now, which is great. And that's the one a number of my patients have.

I think it was November. And so, yeah, we are doing this kind of slow.

So tell people. I don't even think we've mentioned the name of the company. So what's the name of the company?

It's called. Well, 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 KE2 if you wanted to. Leaves it open to the idea that it could be more than just ketogenic diet. And so the company is organized around one, is giving people the information they need through this sensor which links up to an app. Two, 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 ketogenic diet and they're like, well, 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 going to help people get. So you know what to do. You're measuring how well you're doing. But how do you actually, how can you enable that? How can you get people the 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 to this food court and 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, it's like 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 the behavior. So it's been kind of a fun adventure. We'll see.

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. 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 spent 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. If 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. I actually went down there and visited. A friend of mine is the CFO at the company, Ned Siegel, and he invited me to come. 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 invited me to come down. We toured through the facility. I'd never been there before, but I think they have something going there. Talk about increasing scientific literacy. And I know I have 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 hunt in 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 thank you enough. This 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@peterattiamd.com podcast there you'll find the show notes, readings and links related to this episode. You can also find my blog@peterattiamd.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 peteratti amd. But usually Twitter is the best, best way to reach me to share your questions and comments. Now for the obligatory disclaimer. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice and note no doctor patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for pro professional medical advice, diagnoses or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and or advise, please visit Peteratti amd.com forward/about.