#52–Ethan Weiss, M.D: Cardiovascular disease and growth hormone—two surprisingly interrelated topics

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [intro music]

2. 0:04 – 22:23

   Gretzky Jerseys and Hopkins Memories

   1. PAPeter Attia0:04

      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 at peterattiamd.com. [intro music] Hey everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in, one, the podcast itself, and two, 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 and all aspects of it, which includes lipids and the management of blood pressure and the endocrine system, et cetera. But what I found most interesting in this discussion, in addition to just the master's class in understanding everything from acute coronary syndrome to all of the complex nuances around stent placement, which is something that I think anybody listening to this knows at least somebody who's had a stent placed, and to sort of go through all of that literature 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 it was nothing compared to, at least for me, diving into what led him to pursue this field of endocrinology and specifically what he found with respect to growth hormone and IGF. And, 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 spent a great deal of time talking about this, and you could almost think of this as two separate podcasts, one that really deals with cardiovascular disease, specifically interventional radiology and diagnostic techniques. We talk extensively about calcium scores and CT angiograms and things like that that we get asked about all the time. And then there's basically a second podcast here, which is a really interesting discussion around growth hormone, its effect on the liver, the brain, et cetera. Finally, we touch really briefly at the end on a company that Ethan has started quite recently called Keyto or Keytwo, 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 show notes are really gonna be helpful, especially for people who actually want to go back and look through all of the literature and 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. [upbeat music] Ethan, thanks so much for making time today.

   2. EWDr. Ethan Weiss7:31

      Thank you, Peter. Thanks for coming over rainy San Francisco.

   3. PAPeter Attia7:34

      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.

   4. EWDr. Ethan Weiss7:43

      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, I love it. Actually, my kids love it, too. They've staked out their own territory [chuckles] on this one.

   5. PAPeter Attia7:58

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

   6. EWDr. Ethan Weiss8:02

      Yeah. [chuckles] Perfect.

   7. PAPeter Attia8:03

      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, you have in front of me a home jersey circa nineteen eighty-six Edmonton Oilers signed by none other than the Great One.

   8. EWDr. Ethan Weiss8:25

      Yeah. Look, I grew up in Baltimore, which was not really a hotbed of, of hockey. I think they were the Skipjack, minor league hockey team, triple A team, I guess. I don't even-- 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 and a football fan. But my dad had grown up in Chicago and, and really did like hockey. And one year we were back there visiting my grandparents for Christmas. I think it was the winter of nineteen seventy-nine. 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, you know, I basically fell in love with instantly. And at that time, in the late '70s, early '80s, it was, you know, 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 Capitals 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 gonna go to LA. My uncle, y- my brother, my uncle is b- 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, like, a big series of tables with, with a bunch of silent auction items. And I walk 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, you know, buddy, I see you walked by that a few times. Do you have any interest in it?" I said, "Yeah, I've got interest in it, but there's-- I can't, I can't afford that." And he said, "Nah, listen, I'm pretty sure if you bid the minimum, y- you'll get it." And the minim- minimum bid was a hundred dollars. And I said, "You gotta be kidding me. Gretzky played here in LA and how can... That's impossible. It's a signed jersey. It's beautiful. The frame alone is worth more than a hundred dollars." 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 [laughing] I brought it here, and it's, it's awesome as a conversation starter when people come visit.

   9. PAPeter Attia10:32

      What I immediately loved about it was when I was ten, so nineteen eighty-three, 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 fifty dollars. 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 five to ten dollars, and it added up to fifty, and we went-- 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.

   10. EWDr. Ethan Weiss11:15

       Yeah.

   11. PAPeter Attia11:16

       I went with the home jersey, which is the one you have, and it was so big.

   12. EWDr. Ethan Weiss11:21

       Yeah.

   13. PAPeter Attia11:21

       Like, I just couldn't... Y- you know, I just wanted to make sure I never grew out of it, and I probably wore it for, like, you know, every day for three years. [chuckles] The sad thing is I don't have it anymore. I, 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.

   14. EWDr. Ethan Weiss11:39

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

   15. PAPeter Attia11:42

       Yeah.

   16. EWDr. Ethan Weiss11:42

       And you were an Oilers fan?

   17. PAPeter Attia11:44

       I was. I mean, the Leafs were not-- Toronto's such a great hockey town-

   18. EWDr. Ethan Weiss11:48

       Yeah

   19. PAPeter Attia11:48

       ... that, you know, going to games was, I mean, just the greatest highlight of, 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 then it was so unsophisticated that if the game was a blowout, by the third period, you could sneak down into the golds and you could, 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, 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 Oiler glory days. And, you know, it's sort of hard to believe that you could have Gretzky, Messier, Curry, Coffey, Kevin Lowe, Grant Fuhr all on the ice at one point in time.

   20. EWDr. Ethan Weiss12:35

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

   21. PAPeter Attia12:50

       Northlands Coliseum it was.

   22. EWDr. Ethan Weiss12:52

       Yeah.

   23. PAPeter Attia12:52

       Yeah.

   24. EWDr. Ethan Weiss12:52

       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, it's not glamorous. It's certainly not like LA.

   25. PAPeter Attia13:10

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

   26. EWDr. Ethan Weiss13:12

       No.

   27. PAPeter Attia13:13

       Yeah.

   28. EWDr. Ethan Weiss13:13

       No. Or even Vancouver.

   29. PAPeter Attia13:14

       Or Toronto.

   30. EWDr. Ethan Weiss13:15

       Or Toronto or Montreal.
3. 22:23 – 24:25

   How Ethan Chose Cardiology

   1. PAPeter Attia22:23

      So how did you pick cardiology?

   2. EWDr. Ethan Weiss22:25

      Well, again, so the background is I'm a second-generation cardiologist, so in- 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, 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 that some, 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 I, it was my first time in a lab, and I loved it, so I knew I wanted to go back and do that. I ended up basically asking a bunch of people, I said, "You know, is anybody here doing work on the pathogenesis of..." It wasn't called ACS or acute coronary syndrome back then, but, "The pathogenesis of unstable angina or, or MI in young people without risk factors?" So I got pointed to this guy who was a young, at that time, assistant professor, a Belgian guy, who went on later to be the dean of the medical school at the University of Miami, and he had a illustrious academic career. His name is Pascal Goldschmidt. And 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, 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, 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, I'm not entirely convinced I, I know the answer yet." But I ended up eventually deciding that I, I didn't like parents, and so I went down the path of doing adult cardiology.

4. 24:25 – 32:17

   Plaque Rupture, Clotting, and the Cause of Heart Attacks

   1. PAPeter Attia24:25

      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, how would you define all these terms for folks, and what's the framework in which you anchor these things?

   2. EWDr. Ethan Weiss25:00

      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. Ninety-nine p-percent of heart attacks in this country happen because of a ruptured atherosclerotic plaque, so-

   3. PAPeter Attia25:16

      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 ninety-five percent occlusion in the artery on the angiogram, my God, that's just five percent 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?

   4. EWDr. Ethan Weiss25:43

      Yeah. Well, this is what's so amazing is that if you go back not that far in the literature, you'll find articles where people are having a debate about whether the-- So they, they did autopsies on people who presented with sudden cardiac death. So somebody would show up dead from a heart attack. They'd 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? And 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 in people who showed up in the emergency department with, 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 so that was the, 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 fi- back and find it for you. But he described something that stuck with me, which was that if you look at an autopsy of 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 Rena Verani and others have said that a lot of the progression of, 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.

   5. PAPeter Attia27:32

      At the same point in the artery or along different points?

   6. EWDr. Ethan Weiss27:35

      In the same plaque.

   7. PAPeter Attia27:36

      Wow.

   8. EWDr. Ethan Weiss27:36

      So in the same plaque, and so that told-

   9. PAPeter Attia27:38

      So basically a seven-ringed tree.

   10. EWDr. Ethan Weiss27:40

       Yeah.

   11. PAPeter Attia27:40

       On the cover of Starry's pathology book, which is, I've talked about this before, it's sort of one of the most important books I have to explain atherosclerosis to patients, there's actually a picture on the cover that shows a very comparable lesion to that, which is just these concentric rings-

   12. EWDr. Ethan Weiss27:55

       Right

   13. PAPeter Attia27:55

       ... where the final one, you have this big, dark, bloody clot in there-

   14. EWDr. Ethan Weiss27:59

       Right

   15. PAPeter Attia27:59

       ... which was obviously the fatal one.

   16. EWDr. Ethan Weiss28:00

       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, the contents of that plaque, what we're calling this atherosclerotic plaque, it's rich with lipids and inflammatory cells, but it, the thing that causes the heart attack is none of that stuff. It's the, 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, you know, a wound healing signal. So if you cut yourself, we have tissue factor underneath the endothelium, which is that inner lining of our blood vessel, and that's there to sense injury. And when the blood sees tissue factor, the blood ha- there's a biochemical reaction that we've, been described for decades that ends up resulting in a blood clot.

   17. PAPeter Attia28:57

       It's sort of an epoxy. You know those epoxies that come in two separate tubes? Taken alone, they're not sticky, but-

   18. EWDr. Ethan Weiss29:03

       Right

   19. PAPeter Attia29:03

       ... 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-

   20. EWDr. Ethan Weiss29:12

       Yeah

   21. PAPeter Attia29:12

       ... you get this acute brick.

   22. EWDr. Ethan Weiss29:14

       I've been describing it as a substrate and trigger, but I think it, that's a much better-- I like your description. So, and that was, again, a debate not that long ago about what, what the cause of these things was. It eventually, within a ten-year period, we learned so much because it was, I think, nineteen eighty-eight 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. And it wa-

   23. PAPeter Attia29:40

       And tell folks what streptokinase does.

   24. EWDr. Ethan Weiss29:42

       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, 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.

   25. PAPeter Attia30:15

       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, and yeah, if, if it was just a diffuse response, well, you'd kill the organism by clotting everything within the circulatory system.

   26. EWDr. Ethan Weiss30:49

       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 Procoagulant coagulation factors, say, you know, any of the one, you know, factor II prothrombin, you'll get a sick mouse, but the mouse will survive through development. So they will, 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 or 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, the role of the placenta and how placentas don't clot off, and there's just unbelievable, fascinating evolutionary biology that we could spend hours-

   27. PAPeter Attia31:33

       U-unless someone has HELLP syndrome.

   28. EWDr. Ethan Weiss31:35

       Right.

   29. PAPeter Attia31:35

       That becomes this awful exception to that rule where you get these infarcted, clotted placentas, and then the fetus is, is usually underdeveloped, so-

   30. EWDr. Ethan Weiss31:44

       Well, and 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 it end, basically the placenta ends up clotting off.
5. 32:17 – 44:00

   Defining MI, Unstable and Stable Angina

   1. EWDr. Ethan Weiss32:17

      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.

   2. PAPeter Attia32:31

      Let's explain what those three things are. So everybody understands what chest pain is.

   3. EWDr. Ethan Weiss32:35

      Yep.

   4. PAPeter Attia32:35

      You have these classic symptoms that people understand, elephant sitting on chest-

   5. EWDr. Ethan Weiss32:39

      Yeah

   6. PAPeter Attia32:39

      ... radiating into left arm, nausea, that sort of stuff, up into the neck. You mentioned the changes in the electrocardiogram. We'll obviously link to photos of this sort of stuff, but it's hard to do this 'cause we're gonna 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?

   7. EWDr. Ethan Weiss33:17

      That's repolarization.

   8. PAPeter Attia33:17

      Yeah.

   9. EWDr. Ethan Weiss33:18

      Ventricular repolarization.

   10. PAPeter Attia33:19

       Ventricular repolarization.

   11. EWDr. Ethan Weiss33:19

       Yeah.

   12. PAPeter Attia33:20

       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?

   13. EWDr. Ethan Weiss33:32

       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 that the treatment of MI, of heart attack, was to put somebody in bed. And then there was the advent of beta blockers, a couple other blood pressure medicines, which were basically forced, you know, pharmacological bed rest, and then aspirin and then streptokinase, which we talked about, which is basically a 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 ventricles. 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 or 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 a s- 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, they'd have chest pain, but they didn't have this Q wave, and so they were called non-Q wave myocardial infarctions.

   14. PAPeter Attia36:00

       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 'cause we're gonna 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, 'cause it's been so long since I've looked at CK, is they used to even look at a fraction called the MB fraction, which would try to be more specific for cardiac muscle than, say, the muscles in your quads or something like that. So if you had those two things, the pain and the enzyme findings, you were having an MI. The EKG was simply used to determine if it was Q wave completely through or non-Q wave. Is that right?

   15. EWDr. Ethan Weiss36:54

       Mostly. I mean, the EKG is, 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 twenty years, and we can touch on that a little bit. But the EKG is, 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, 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.

   16. PAPeter Attia37:43

       And that was differentiated from stable angina based on what?

   17. EWDr. Ethan Weiss37:46

       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, of, you know, Fred Sanford talking about him 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, 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 increased demand. Sometimes people call it demand ischemia. And so the idea was that if you have this blockage that's seventy-five, eighty percent 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.

   18. PAPeter Attia39:13

       That's why people are told to take nitroglycerin if they're having chest pain.

   19. EWDr. Ethan Weiss39:16

       That's right. But the problem is, if you've got a fixed lesion there that's full of a calcified plaque with a bunch of different lipids and stuff in there, you can't really dilate. You can dilate the proximal segment before the blockage or you can dilate the distal segment after, but you can't really deliver more. 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 steal. 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.

   20. PAPeter Attia39:55

       That's actually the best explanation I've ever heard for it. Understanding the fact that I'm, 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-

   21. EWDr. Ethan Weiss40:18

       Yeah

   22. PAPeter Attia40:18

       ... 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.

   23. EWDr. Ethan Weiss40:35

       That ties in together with sort of the way symptoms develop, the chronicity of the problem, the fact that, you know, 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 a-acute thing. So just to kind of put this in, 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 fifty, 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 seventy percent. Conveniently, it's also the point when stress tests, whatever flavor you like, also begin to be able to detect coronary disease. So we, we have focused, I think, a lot of energy on this seventy percent number because it's what we can measure clinically, either through symptoms or through our testing. But there's nothing to suggest that there's a magic in that number that would put somebody at a greater risk as opposed to somebody who had a, you know, fifty percent. And in fact, if you go back over time and again to the work of Michael Davies, I think, and I don't want to misspeak here, but I think a lot of the fatal plaque rupture events that happened in this series of people who came in and died happened in, in arteries that had only thirty or forty percent.

   24. PAPeter Attia42:28

       I think that's actually correct. And I, 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 priority to predict which one of these things was going to be the fatal one. You could have these ninety percent 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, so you know, someone who's walking around with a ninety-five percent stenosis is very likely to suffer death in the case of that plaque rupturing. Of course, that's still a harbinger for what's going on elsewhere in the heart. So there obviously, you know, very few people are walking around with a single point of this injury. It's telling you that there's probably injury throughout the heart and that they could die from another one. But that to me, which I want to come back to, right? Because I want to talk in depth about some of the diagnostic tools that we have, especially to predict who's at risk, who's not at risk. And this is becoming increasingly more important as we have to decide both on the risks and costs of treatment as the treatments get more and more elaborate. And this ability to predict who's going to have a fatal MI versus who's not, I, I'm not convinced we're that much better at it today than twenty years ago, are we?

   25. EWDr. Ethan Weiss43:54

       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.

   26. PAPeter Attia44:00

       Yeah.

6. 44:00 – 49:58

   Modern ACS Nomenclature and Emergency Treatment

   1. PAPeter Attia44:00

      Let's go to where we are today. So we've talked about Q wave, non-Q wave. Talk to me about what is the nomenclature today?

   2. EWDr. Ethan Weiss44:04

      This nomenclature evolved over the past fifteen or twenty 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, the seg-- there's then a line, a direct line, a flat line that connects the end of the S wave to the beginning of the T wave, and that we call the ST segment. And that is usually isoelectric, isoelectric with the rest of the, of the EKG. In other words, it's, 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 f- couple of millimeters, and it does so in more than one lead, that that signaled that there was a block, 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 Braunwald and other people in the TIMI 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.

   3. PAPeter Attia45:49

      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 in some of the Q waves, but not all of them did?

   4. EWDr. Ethan Weiss46:02

      Yeah, I think that's the right thing. So the way, 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 'cause that was what came later. The non-Q wave MI w- 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.

   5. PAPeter Attia46:34

      Which is just not as easy to say as non-STEMI.

   6. EWDr. Ethan Weiss46:37

      No. No. So acute coronary syndrome, I think, the way I d- tell the, teach the students is acute coronary syndrome is the entire collection. It's everything, and it includes STEMIs, non-STEMIs, 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 that, 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 nine one one, activate the cath lab. This patient goes straight in. They get heparin, they get aspirin, they get all the other things, clopidogrel.

   7. PAPeter Attia47:37

      And just to be clear, do we even check enzymes in those patients?

   8. EWDr. Ethan Weiss47:40

      No.

   9. PAPeter Attia47:40

      Or we're not, we don't care?

   10. EWDr. Ethan Weiss47:41

       No. So it's an immediate thing, and in fact, when I-- 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 Braunwald coined this term, time is myocardium, since we understand that the longer the, the heart is deprived of oxygen, the less chance that it's gonna actually recover, there's been a push to speed things up. And so now there's-

   11. PAPeter Attia48:09

       So the ER can now make that call.

   12. EWDr. Ethan Weiss48:12

       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.

   13. PAPeter Attia48:26

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

   14. EWDr. Ethan Weiss48:28

       I hear about it-

   15. PAPeter Attia48:28

       Or maybe on the way out.

   16. EWDr. Ethan Weiss48:29

       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, fifteen years ago, uh, this cardiology fellow had to make that call.

   17. PAPeter Attia48:39

       How much time has that saved if you think about where we are today versus ten years ago? Is that a, that's a half an hour savings potentially.

   18. EWDr. Ethan Weiss48:45

       Maybe. Maybe. I mean, every hospital now in this country is measuring their what's called door to balloon time, so, or door to open artery time. It's a quality metric. And like every quality metric, 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, you know, DNR, DNI, or have metastatic cancer, or there are other things that you don't have the time to have a nuanced conversation, and you're not having a conversation with an expert. So there is a trade-off, but the overall net-net, I think there's, our society of people, citizens and cardiologists and other people and emergency room doctors all, I think all agree that this is, 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. And since we're-

   19. PAPeter Attia49:32

       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, right way to do things? That opening the artery in the STEMI patients is gonna save lives.

   20. EWDr. Ethan Weiss49:42

       I'd have to go back. It was probably one of the early TIMI 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.

7. 49:58 – 1:06:35

   The Cath Lab, Stents, and Antiplatelet Therapy

   1. PAPeter Attia49:58

      Can you explain just, I mean, there's gonna be a lot of people listening to this who won't necessarily know exactly what we mean. So when a patient goes into a cath lab-

   2. EWDr. Ethan Weiss50:06

      Yeah

   3. PAPeter Attia50:06

      ... what actually happens?

   4. EWDr. Ethan Weiss50:08

      So again, a little bit different today than it was in the old days 'cause in the old days, almost everybody had basically a needle put into the femoral artery. So the femoral artery is a, is a major offshoot of the aorta, feeds your leg oxygen.

   5. PAPeter Attia50:20

      You go into the crease in the groin and you can, anybody can feel their pulse there. So if you feel that, that's your femoral artery. That's about the size of your, you know, somewhere between your pinky and your middle finger. I mean, that's a monster artery, and you're putting a catheter in there.

   6. EWDr. Ethan Weiss50:35

      There's a technique called the modified Seldinger 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 cat- catheter, which I think is like two millimeters. You thread that in. You can then under X-ray guidance with a wire to make it a little stiffer, guide it all the way up around the arch of the aorta and back down.

   7. PAPeter Attia51:09

      We'll have a figure of this for sure so people can see what that does.

   8. EWDr. Ethan Weiss51:12

      Back down to the base of the heart where the coronary ostia are. So they're, in normal human beings, there's a left coronary ostium and a right coronary ostium, and you can put that catheter and engage it, and then that allows you to inject contrast dye, which under X-ray will allow you to actually see the artery or see at least the inverse of what the artery looks like. And then what people 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 reestablish blood flow.

   9. PAPeter Attia51:55

      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 at the le- you know, you described an incredibly complex chemical reaction that is taking place, and one of our solutions is chemical, right? We can inject something that can break apart the epoxy, but also we can put a balloon in and use that balloon to inflate open and try to crack it open, and as you'll mention in a moment I'm sure, you can put in these metallic things that spring open called stents.

   10. EWDr. Ethan Weiss52:28

       It's such a good point, Peter. I mean, it's really, it's as if you went to a, a stream and there were a beaver dam there and you just take a bulldozer or you take a shovel and just shovel all of it downstream. And so, uh, you know, 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 of that crap downstream, and does that have an effect on smaller blood vessels or smaller areas of muscle that end up getting occluded by all this stuff that you elaborate downstream when you're blowing open this artery? It 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 that dissolve clots.

   11. PAPeter Attia53:13

       So the mechanical versus the chemical treatment.

   12. EWDr. Ethan Weiss53:15

       That's right.

   13. PAPeter Attia53:15

       Yeah.

   14. EWDr. Ethan Weiss53:16

       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'd 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, 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 pr- primary angioplasty again became standard of care in this country.

   15. PAPeter Attia53:55

       Because while the epoxy process requires two things and therefore is highly specific and be localized, the clot busting is not.

   16. EWDr. Ethan Weiss54:03

       No.

   17. PAPeter Attia54:03

       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's going to see it.

   18. EWDr. Ethan Weiss54:13

       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 'cause as you say, circulation is circulation, right? I mean, it doesn't take that long for something that's in part, in 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 most, almost all US hospitals now, it's primary angioplasty. And so after you mentioned these stents, these little metal scaffolds, they developed back in the 1990s as a means of treating stable angina. So if somebody came in and they were having stable angina, so they said, "God, you know, Doc, I'm walking up the hill and I get this, you know, burning in my chest and I sit down and it goes away and I can't, now I'm just not able to walk anywhere, so what can we do?" Well, people realized 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 forty, fifty, sixty percent 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 cause when you blow up the balloon. So people thought, "Well, gosh, if you could leave this metal scaffold behind, you could actually improve the likelihood that it's not going to restenose." So stents completely cured the physical recoil problem, which I think, you know, again, I don't know the exact number, but it was some non-zero number. But they left behind this other problem, which was the injury problem. And so what people realized was that in the act of blowing up the 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 in-stent restenosis or ISR, in-stent 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 a like- some likelihood that they'd come back within three to six months with recurrent symptoms, and you'd do a stress test, you'd see that there was, looked like there was 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 in-stent restenosis. We went through this entire period of, you know, five or seven years of trying to find ways to solve restenosis, including radiating the inside of the vessel wall. So, 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, and we can talk about those, but you probably already talked about them a bunch.

   19. PAPeter Attia57:31

       Well, no, no, actually, I was just, 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?

   20. EWDr. Ethan Weiss57:48

       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 I, 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 used to treat cancer. And so again, I, 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, they're making scar tissue. And so somebody realized, gosh, if you apply this, 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 ca- used to call in-stent restenosis. For the most part, now that problem is no longer.

   21. PAPeter Attia58:59

       And there was a bit of a hiccup in '05, '06, '07 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-eluting stents to come back. And I recall that they even, at one point, even Boston Scientific and Abbott had the same stent, identical, but branded under different names. I mean, it was such an interesting time in the cardiology world.

   22. EWDr. Ethan Weiss59:31

       I don't remember all the details. I remember the, a lot of these reps from these companies were in the cath lab, and there was a big battle to get market share in these different stents. And there were other things besides which drugs were on the stents. There were issues around deliverability and how stiff they were and how long, you know, all these other things. And so it was a, you know, as a general cardiology fellow and somebody who was interested in basic science, I wasn't paying attention to the nitty-gritty of kind of what was going on in this war for market share, but, but there definitely was a lot going on. The biggest problem with these drug-eluting 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 a series of trials where people tried aspirin. I believe they tried warfarin. They tried everything, and they actually couldn't-

   23. PAPeter Attia1:00:27

       So aspirin and warfarin are both blood thinners through different mechanisms.

   24. EWDr. Ethan Weiss1:00:31

       That's right. So aspirin acts on platelets, warfarin blocks that coagulation cascade, you know, downstream of tissue factor. But, but people couldn't use these stents for a while. And then in 1996, and I know this 'cause I, as a medical student, had the ridiculously good fortune of, of being the first author on a, a paper that was published in the New England Journal of Medicine. In that same issue-- So our paper was, is forgotten mostly, except for me. But in that same issue, and I looked at it the other day, was a trial that demonstrated that you could do stenting of coronary arteries safely with the addition of this drug that's no longer used 'cause it had toxicity called ticlopidine, Ticlid. And so Ticlid was the first generation of these what we call thienopyridines. 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 in- interventional cardiology, is if you gave people this drug, Ticlid, 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. It's just a different drug.

   25. PAPeter Attia1:01:47

       And patients might know that drug by a different name.

   26. EWDr. Ethan Weiss1:01:50

       Plavix.

   27. PAPeter Attia1:01:50

       Yeah.

   28. EWDr. Ethan Weiss1:01:50

       Right.

   29. PAPeter Attia1:01:51

       So today, when a patient gets their stent, they also get a, uh, what? A year's supply of Plavix? How long do we keep it on?

   30. EWDr. Ethan Weiss1:01:57

       Yeah. So where I was going with that was that there was this thing called subacute stent thrombosis. So thrombosis is the, 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 'cause it's a complete stoppage of blood flow, and it's critical, and people can die.
8. 1:06:35 – 1:29:33

   COURAGE, ORBITA, and Stents for Stable Angina

   1. PAPeter Attia1:06:35

      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, 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. Weiss, God, it's just every time I get on that treadmill, I just get a tightness in my chest, and the other day I was walking up the street and it was really steep," and blah, blah, blah, blah, 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?

   2. EWDr. Ethan Weiss1:07:42

      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 blocker. So beta blocker helped reduce the demand. So basically it's like putting a governor on, 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, 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 'cause there was no other option for what we now call re- 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.

   3. PAPeter Attia1:08:35

      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, uh, beautiful blood sources and you just attach it what we call distally, so past the lesion. And, and by the way, if my, my memory is correct, it was only Lima to LAD. It wasn't Lima to circ. It wasn't Rima to right main. There was nothing else. They did sham surgeries, if I recall, to demonstrate that.

   4. EWDr. Ethan Weiss1:09:36

      I don't know if they did sham surgeries back then, but you're absolutely right. It was only Lima to LAD and it was only a subset, right? So I think it was you had to have multi-vessel disease, left ventricular dysfunction, diabetes. I mean, there were a subset of people. It was not everybody got a mortality benefit. I'd have to go back and look at the-

   5. PAPeter Attia1:09:51

      Maybe those weren't the shams, but I, I know there were some sham surgeries that involved sternotomies, which when you think about that, I mean [chuckles] 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 LAD 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?

   6. EWDr. Ethan Weiss1:10:18

      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 talk, 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? So mortality. And, 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.

   7. PAPeter Attia1:10:56

      And people sometimes poo poo that, but I, I think it's important, at least for me, I like to dispel that 'cause there's certainly a, a, I find a, 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.

   8. EWDr. Ethan Weiss1:11:14

      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, there are a lot of things that we're-

   9. PAPeter Attia1:11:23

      Can't have sex.

   10. EWDr. Ethan Weiss1:11:24

       Yeah. No, yeah. Yes. And all that stuff I think is incredibly important and it, it shouldn't just because you're not conferring a mortality benefit, all-cause mortality benefit, doesn't mean that there's not benefit. So I think that the advent of the stent era was, was remarkable. It happened to coincide with the advent of the statin era, right? So the first statin, Lovastatin, was approved in nine- 1988, I believe. So remember I had said that we were treating people with, 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 gonna become a, an important mainstay of treatment of people with stable coronary disease as well.

   11. PAPeter Attia1:12:05

       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, uh, feel free as well.

   12. EWDr. Ethan Weiss1:12:26

       So let's back up and just make sure we reemphasize, 'cause I don't think this point cannot be emphasized too many times. So if you show up in the hospital or in the emergency room or anywhere in the world with a s- ST elevation MI, a STEMI, in other words, that ST segment is increased above baseline and you're having a heart attack-

   13. PAPeter Attia1:12:42

       Yeah. It's a do not pass go, do not collect $200. You're going straight to the cath lab.

   14. EWDr. Ethan Weiss1:12:46

       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, a isoform of for, 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 does, is not ST elevation, anything other than ST elevation. It could be normal. That puts you into a different category. And mostly in the United States, the management of non, depending on a couple of factors, but most people are managed either what's called medically, so with a bunch of medicines, or they go down a path of interventional cardiology. So-

   15. PAPeter Attia1:13:37

       Now let me ask you a question, Ethan. 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?

   16. EWDr. Ethan Weiss1:14:07

       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 medicines, 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 sixty 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 noninvasively 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, 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 more 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, the things start to become a little bit more gray. And then stable angina, which is the last thing we'll, we'll come back to, there's a huge amount of gray area, again, about mortality, not, not symptoms.

   17. PAPeter Attia1:15:41

       So let's talk about ORBITA. What did that trial look at? What question did it try to answer?

   18. EWDr. Ethan Weiss1:15:46

       This trial was published in November of twenty seventeen, I believe, and it was done by a group in London who I had never heard of before this, this trial came out. I guess, uh, Daryl Francis is, 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, in that world. This trial shook the world. Actually, we should probably talk about COURAGE before we talk about-

   19. PAPeter Attia1:16:08

       Let's do that. Yeah, thank you. Let's go b- 'cause I alluded to COURAGE, and then we got off topic. Tell me about COURAGE.

   20. EWDr. Ethan Weiss1:16:12

       So COURAGE was published in two thousand and seven.

   21. PAPeter Attia1:16:15

       And if anybody asks me what COURAGE stands for, I don't remember.

   22. EWDr. Ethan Weiss1:16:17

       I don't remember either.

   23. PAPeter Attia1:16:18

       Yeah. But it's, it's an acronym that is put together to explain what the trial was about.

   24. EWDr. Ethan Weiss1:16:23

       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-

   25. PAPeter Attia1:16:54

       By the way, I'm just going to interject. So I'm going to make a plug for one of my favorite apps, which is incredibly dorky. It's called Trials. I don't know if you've seen this app, but let me show it to you, and we'll make sure we link to it. So the-- Oh, sorry. The, 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's, 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 major points. So it's called Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation, parentheses, COURAGE. And then it goes through and explains everything about it. So if you're listening to this and you're a physician and you don't have this app, get it, and truthfully, even if you just have a, 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 twenty minutes to kill and I'm kind of bored and it's, you know, I'm in the, I'm on the runway and it's taking 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.

   26. EWDr. Ethan Weiss1:18:09

       Well, now you can read it and see how close I am.

   27. PAPeter Attia1:18:11

       Yeah [laughs] . Well.

   28. EWDr. Ethan Weiss1:18:12

       So I'll try to be, I will be, uh, be intentionally less detailed about how [laughs] I, 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 m-maximum medical therapy to stenting in patients with stable coronary disease. And the idea was, is there a benefit in terms of reducing the risk of heart attack or some other heart outcome like death in patients when you randomly assign them in a non-blinded manner to be treated with maximum medicines or stents?

   29. PAPeter Attia1:18:39

       Non-blinded meaning they did not do sham procedures-

   30. EWDr. Ethan Weiss1:18:42

       That's right
9. 1:29:33 – 1:40:30

   Uncertainty, Evidence-Informed Medicine, and Preventive Cardiology

   1. PAPeter Attia1:29:33

      Yeah, it's probably just the composition of those patients is probably migrating constantly. And 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.

   2. EWDr. Ethan Weiss1:30:19

      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 it, then 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 results of these experiments, whether they're experiments in a lab with 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 95% chance that it didn't happen by chance, but there's a 5% chance that 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 expectation.

   3. PAPeter Attia1:31:14

      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, 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, 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 'cause that comes back to it. So I think the listeners know what a calcium score is and a CT angiogram is, but so just give this the quickest sense of that 'cause I'm-- what I'm much more interested in is what do the results tell us?

   4. EWDr. Ethan Weiss1:32:23

      As a cardiologist practicing in twenty nineteen, 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, as I can, picking up every rock and looking under everything and, you know, 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, you know, somebody would come in from an outside hospital sick as shit, just absolutely on death's door, and all we did was just turn off everything, and the patient got better 'cause 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, right? A lot-- the, 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, you know, "What's my risk of dying from a heart attack?" Or, uh, "My brother died of a heart attack at forty-four. 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 d-don't now yet have the tools to be able to say, "You know, Peter, well, your risk is X, Y, or Z, and so therefore we should do this or this or this in terms of prevention," understanding that there's going to be risk in each one of these things that we do and there may be risk in even part of the process of getting from here to here, point A to point B. So-

   5. PAPeter Attia1:34:10

      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 two point O. 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, uh, 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 have-- 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.

   6. EWDr. Ethan Weiss1:35:51

      A hundred percent. 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.

   7. PAPeter Attia1:36:09

      And I feel the same way. I mean, prevention is not really amenable to this idea of medicine two point O, which is clinical trial, average outcome, short duration, simple intervention, easy to measure outcome.

   8. EWDr. Ethan Weiss1:36:23

      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, I joke that like a prevention trial, the kinds of trials that I want to do would take fifty or sixty years. How do you convince somebody I'm about to be fifty? 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 be-- 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 (a) was something that 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 ten years ago, I would say, I, "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, like, safety belt of, of evidence basis that we're used to, right? There's not going to be a ORBITA-like trial to help me decide whether I should be aggressive with lipid lowering in a thirty-five-year-old. That's not going to happen with primary prevention. So-

   9. PAPeter Attia1:37:36

      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, 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.

   10. EWDr. Ethan Weiss1:37:50

       Mm-hmm.

   11. PAPeter Attia1:37:50

       And to me, the latter just makes much more sense.

   12. EWDr. Ethan Weiss1:37:53

       I love it.

   13. PAPeter Attia1:37:53

       Because these decisions that you have to make virtually every day, and I, I, 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, 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.

   14. EWDr. Ethan Weiss1:38:26

       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, but it's difficult in that we only know success by the absence of failure. So there's no one who's gonna come to me tomorrow and say, "Gosh, Ethan, thank you for the fact that I've-- I'm forty-six, that I did not have a heart attack again this year." Just doesn't happen, right?

   15. PAPeter Attia1:38:49

       [laughs] That's a great way to explain it.

   16. EWDr. Ethan Weiss1:38:50

       Whereas the other way around, like I've had a few patients-

   17. PAPeter Attia1:38:53

       But if you're an orthopedic surgeon, for example-

   18. EWDr. Ethan Weiss1:38:55

       Exactly. That's right

   19. PAPeter Attia1:38:55

       ... you break your leg, you fix it.

   20. EWDr. Ethan Weiss1:38:57

       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, you know, I was not as aggressive as I could have been, but probably still following the sort of guidelines, is that gonna guide me as a physician to be more aggressive in the future? And again, we're not gonna have clinical trial data to help us here. This is all art and judgment.

   21. PAPeter Attia1:39:54

       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.

   22. EWDr. Ethan Weiss1:40:13

       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, in making these decisions? I mean, that's where things get really interesting.

   23. PAPeter Attia1:40:26

       And there are other physicians, because typically these are not just discussions between two people.

10. 1:40:30 – 1:51:08

    Calcium Scores and What Zero Really Means

    1. PAPeter Attia1:40:30

       So what's a CAC? What's a CTA, and how do you use them?

    2. EWDr. Ethan Weiss1:40:34

       The way I break this down is there's anatomy, so anatomic tests and their physiologic tests. So physiologic test would be like a stress test, a tr- 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 just 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 forty years. In the past twenty 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, I should have an angiogram." No symptoms, just, "I want to have an angiogram. I want to know that I don't have any-"

    3. PAPeter Attia1:41:38

       Right. Just a preventative, get a baseline.

    4. EWDr. Ethan Weiss1:41:40

       Yes, which is very much like I want to make sure I don't have colon cancer or breast cancer. And it-- 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, and what I tell people is that the, 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 medi- medical therapy? And, and what they are, are they are triggers for basically saying yes or no to statins, or yes or no to statins and PCSK9 inhibitors. 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 Agoston, and he came up with this idea so people could see on chest X-rays back, you know, a hundred years, that if somebody had a, 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 peak, uh, opaque. So people realized that these arteries, again, by autopsies and other conventional imaging, that these arteries get calcified as they develop more plaque. And so this, 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 it, 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.

    5. PAPeter Attia1:44:02

       It's worth pausing for a moment to make sure, 'cause I, this is a discussion I tend to have with patients a lot, which is what does it mean if it shows nothing, meaning your score is zero? What does it mean if it shows anything that's not zero? And to explain this to patients, I usually have to, again, pull out the pathology textbook and explain all of the things that happen before you would see calcification. So when you look at the stages of lesions, calcification is a very late process. You described it earlier as basically the repair of damage. So if you have a calcium score of zero, does it mean you have perfect coronary arteries? You can't conclude.

    6. EWDr. Ethan Weiss1:44:41

       Yeah, this is a really important point, and, 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 gonna have a calcium score of zero. It's meaningless for her.

    7. PAPeter Attia1:44:58

       Right. 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.

    8. EWDr. Ethan Weiss1:45:08

       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 below one percent. I mean, again, let's remember that the biggest risk factor for having a heart attack is your age. So age supersedes everything else. It supersedes all the other known risk factors that we use every day, your lipids, your blood pressure, the presence or absence of diabetes.

    9. PAPeter Attia1:45:34

       Although I will throw in my, my rant here.

    10. EWDr. Ethan Weiss1:45:36

        Okay.

    11. PAPeter Attia1:45:37

        Why is age the greatest risk factor?

    12. EWDr. Ethan Weiss1:45:39

        I don't know. It's a good question. [chuckles]

    13. PAPeter Attia1:45:41

        I mean, I would argue, as Alan Sniderman has argued, that it's an area under the curve issue. It's an exposure question. So age is the greatest risk factor for a number of diseases in which it's not entirely clear why, but I think in atherosclerosis, you would have to argue that this area under the curve shows a monotonic progression in an individual, just as we see progression of polyp to cancer in the colon. So that's exactly why I think the older you are, the more interesting it is to have a zero calcium score. It's Bayes' theorem at its finest. You are acquiring more and more information as somebody goes on. So, you know, when I see 35-year-olds with zero calcium scores saying, "See, I'm totally fine," I say, "I have no goddamn clue. How do you know that?"

    14. EWDr. Ethan Weiss1:46:27

        But the contrast is that if you see a 35-year-old who does have calcium-

    15. PAPeter Attia1:46:30

        That's exactly right

    16. EWDr. Ethan Weiss1:46:31

        ... that's informative.

    17. PAPeter Attia1:46:31

        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, ding, ding. If you're in the other two quadrants, I don't think I've learned anything.

    18. EWDr. Ethan Weiss1:47:01

        Mostly. So I started, again, I'll frame this as I started off thinking there was no value to calcium scans. I evolved to think, all right, well, there, there's gonna be value in these two quadrants you describe. I also think there's probably some value in, in the extremes in, say, I saw a patient recently who was in his 50s, early 50s, who had a, you know, calcium score of 1,300. You know, asymptomatic, primary prevention.

    19. PAPeter Attia1:47:23

        I have a 49-year-old who just scored 4,500.

    20. EWDr. Ethan Weiss1:47:26

        Right. So that, I mean, that to me is useful, right? So that takes us, again, not gonna ever be supported by clinical trials, but that takes us from, okay, well, now we all agree that you should be on st- at least statin for primary prevention, but, but maybe we wanna be even more aggressive, right? And so that's when you start thinking this is actually gonna change what we do or change, at least in my head, the risk-benefit ratio.

    21. PAPeter Attia1:47:48

        Anecdotally, I want to tell you about that patient because this is, this, 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 (a) ."

    22. EWDr. Ethan Weiss1:47:59

        Right.

    23. PAPeter Attia1:48:00

        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 (a) for sure." You do an advanced blood test on him, normal Lp (a) , 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, 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.

    24. EWDr. Ethan Weiss1:48:40

        Right.

    25. PAPeter Attia1:48:40

        'Cause 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 c- 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.

    26. EWDr. Ethan Weiss1:49:01

        I had a patient I talked about a lot on Twitter a couple weeks ago who ended up, was in his early 50s and ended up having, like, a very, very tight proximal left main. Like, just the kind of thing that you-

    27. PAPeter Attia1:49:10

        The so-called widow maker

    28. EWDr. Ethan Weiss1:49:11

        ... you look at this thing, and you think, "There's no way in the world this guy should have walked into my office," and he did. And his first pass lipids were all completely normal. You know, his, you know, regular fasting lipid. He had no obvious risk factors, and then we got his Lp (a) back, and it was high, and I was relieved. And I was relieved because on the one hand, I, 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.

    29. PAPeter Attia1:49:38

        But at least we've got a couple of indirect things till Sam Tamikris' ASOs are around. Did you look at his aortic valve yet?

    30. EWDr. Ethan Weiss1:49:44

        It's normal.
11. 1:51:08 – 2:01:07

    CT Angiograms, Radiation, Cost, and HeartFlow

    1. PAPeter Attia1:51:08

       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.

    2. EWDr. Ethan Weiss1:51:40

       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 IVUS 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.

    3. PAPeter Attia1:52:18

       That's right. Luminal narrowing is a very, very late consequence of atherosclerosis.

    4. EWDr. Ethan Weiss1:52:23

       Very late. 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 and sort of lumpy bumpiness. But, but you'll see plaque, and that plaque grows down before it grows up. You know, there's a ton of information. The question, of course, is what is the value of that information and how does it change our management? That's, uh, the-

    5. PAPeter Attia1:52:44

       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? E-even IVUS could miss plaque or vulnerability. But it makes you feel a bit more comfortable that your level of aggression can be lower and, and the converse then is true as well.

    6. EWDr. Ethan Weiss1:53:13

       So then what's the cost, right? So other than the theoretical cost of, of the radiation, which is probably something, and the-

    7. PAPeter Attia1:53:20

       Yeah, right now they're going so fast. These things are at a, a, a really good scanner, so the, the top shelf scanners here are doing CT angiograms at about two millisieverts of radiation. So for the listener, millisievert's 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 one millisievert over the course of a year. Living in Denver probably exposes you to four or five millisieverts for a year. So that puts the two millisieverts in context. The first generations of these, Ethan, 20 millisieverts just for a CT angiogram.

    8. EWDr. Ethan Weiss1:54:04

       What's a chest X-ray?

    9. PAPeter Attia1:54:05

       Incredibly low. It's less than one millisievert.

    10. EWDr. Ethan Weiss1:54:08

        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.

    11. PAPeter Attia1:54:16

        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, it's not trivial. It's probably, you know, $2,000, $2,500. So it's a, it's a quite expensive study relative to the CT. The calcium score, which I got to put a plug in, by the way. Your institution here needs to get its head out of its ass.

    12. EWDr. Ethan Weiss1:54:31

        [laughs]

    13. PAPeter Attia1:54:32

        I mean, Jesus.

    14. EWDr. Ethan Weiss1:54:34

        I send patients to Stanford.

    15. PAPeter Attia1:54:35

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

    16. EWDr. Ethan Weiss1:54:41

        Don't get me started.

    17. PAPeter Attia1:54:42

        Yeah.

    18. EWDr. Ethan Weiss1:54:42

        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 example.

    19. PAPeter Attia1:54:46

        I have to send patients from San Francisco to drive down to Stanford. They're pissed off, but I'm like, you know.

    20. EWDr. Ethan Weiss1:54:51

        I tell my patients, this is the one example 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, there's a market.

    21. PAPeter Attia1:55:09

        It's a fixed cost is already sunk and there's no variable cost. It's just, yeah, it's comical.

    22. EWDr. Ethan Weiss1:55:13

        The question then is sort of what is the risk of the CTA? And so from my perspective, the risk is with the right patient and the right doctor is zero. The wrong patient and 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 sur- cancer sur-surgery who just basically said, "Get this tumor the hell out of me. I don't, I don't want cancer anymore. Get it out." And Even though, you know, prostate cancer is a great example, right? There are lots of ways to treat prostate cancer today, and some of them involve cutting the tumor out. Others that are equally as effective probably or close don't. But some people mentally can't get their head around living with cancer, and I think I have patients of mine who when they get a CTA and they see there's plaque there, they just can't sleep because they think, "This thing is going... I'm going to die from a heart attack." And no matter what we say, no matter what I say, it c- I can't dissuade them of that. That to me is the one cause. So that's where I would sort of say this is why I'm not gonna... That and the economic thing is sort of why I'm not gonna widely do this in everybody. But in certain people, it's spectacular.

    23. PAPeter Attia1:56:22

        So before we leave this, let's just talk about what HeartFlow is because that's something that's come on the scene in about the pa- 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?

    24. EWDr. Ethan Weiss1:56:41

        I'm gonna try and keep it brief 'cause I, I got quoted in an article over the summer about HeartFlow, 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 HeartFlow in." So I, I don't want to be too harsh on, 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 you... 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 gonna be faster, and there would 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 doesn't... It's hard to, 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.

    25. PAPeter Attia1:57:55

        So fractional flow reserve is the calculation-

    26. EWDr. Ethan Weiss1:57:59

        Mm-hmm

    27. PAPeter Attia1:57:59

        ... of P2, which is the pressure beyond the occlusion, over P1.

    28. EWDr. Ethan Weiss1:58:05

        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, it doesn't. It goes... It'll go down.

    29. PAPeter Attia1:58:20

        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 stood for again. What did those studies show?

    30. EWDr. Ethan Weiss1:58:33

        The take home, and th- 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 .8, so you use a mathematical formula to basically calculate, and if it was less than .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 co- colleagues have been using it that way for the past few years. Again, there are questions. I don't want to get into the controversy, 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 a vasodilator knot, and, and they can do this and-
12. 2:01:07 – 2:15:27

    Growth Hormone, the Sexually Dimorphic Liver, and Fatty Liver

    1. PAPeter Attia2:01:07

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

    2. EWDr. Ethan Weiss2:01:56

       Yeah.

    3. PAPeter Attia2:01:56

       Whose office is this?

    4. EWDr. Ethan Weiss2:01:58

       I came here to San Francisco twenty-one 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 wanted 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 I, 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, the system for the two sexes differently.

    5. PAPeter Attia2:03:06

       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 bl- women have lower blood pressure. Another one is iron. Women have less iron for thirty, forty 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 prothrombotic response. That's, that's it. I can't believe I didn't even know that.

    6. EWDr. Ethan Weiss2:04:04

       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 s- 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, they're a little bit more susceptible to bleeding, you know. And, you know, 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, and the, the reason it was particularly interesting was that w- 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 m- 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 onto, 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, 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, th- there's a set of genes that are expressed dramatically different, even up to a hundredfold 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 fe- 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, like, basically try and understand if, how this happens. So what regulates the dimorphism of liver gene expression in mammals? It turns out it's not sex hormones. That's actually secondary. It turns out that it's a dimorphic pattern of growth hormone secretion. So it was described back in the fifties and sixties 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, in a beautiful paper, I think it was published in nineteen eighty-two in Cell by Richard Palmer's group. It was found that that factor is, is growth hormone, and that if you in-

    7. PAPeter Attia2:06:25

       Which by the way, is the last one I would have predicted. Like I would have said, "Oh, it's probably luteinizing hormone or follicle-stimulating hormone." I wouldn't have guessed growth hormone.

    8. EWDr. Ethan Weiss2:06:32

       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-

    9. PAPeter Attia2:06:41

       So the guys have these spikes that are less frequent, and the women are putting... Now, area under the curve, about the same.

    10. EWDr. Ethan Weiss2:06:48

        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 hormone, 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 it-- 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.

    11. PAPeter Attia2:07:15

        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, 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? 'Cause you would have suppressed the pituitary secretion?

    12. EWDr. Ethan Weiss2:07:47

        Yes. You should.

    13. PAPeter Attia2:07:48

        Have you done that experiment?

    14. EWDr. Ethan Weiss2:07:50

        In people?

    15. PAPeter Attia2:07:50

        No, in mice.

    16. EWDr. Ethan Weiss2:07:51

        Yeah.

    17. PAPeter Attia2:07:51

        Okay.

    18. EWDr. Ethan Weiss2:07:52

        Oh, yeah, yeah. Yeah, we did that experiment. So I got into this because I was interested in clotting, and, you know, that makes sense as a cardiologist. I just ex- 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, 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 hormone. So downstream of the receptor growth hormone binds, uh, Jak2 basically allows this signal to be transduced.

    19. PAPeter Attia2:08:42

        Is there a different receptor for growth hormone in the liver versus outside of the liver?

    20. EWDr. Ethan Weiss2:08:45

        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 one cytokine receptor. It 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. He-- actually, he was the only person working in the lab at the time. It was just the two of us. And he came to me, he said, "Ethan, there's something wrong with these livers." I don't even need to genotype them, and I'll show you a picture. But it turns out that the livers in the animals where we had selectively deleted Jak2 in hepatocytes were basically turned into adipose tissue. It was the most-

    21. PAPeter Attia2:09:36

        So you were creating NAFLD?

    22. EWDr. Ethan Weiss2:09:37

        Yes.

    23. PAPeter Attia2:09:38

        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.

    24. EWDr. Ethan Weiss2:09:55

        That's right.

    25. PAPeter Attia2:09:56

        And if you do that, you accumulate fat in the liver.

    26. EWDr. Ethan Weiss2:10:00

        Twenty-five fold increase in-

    27. PAPeter Attia2:10:01

        Twenty-five fold. It-- so this-- it, it becomes clinically grotesque. I mean, you just basically create foie gras.

    28. EWDr. Ethan Weiss2:10:06

        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."

    29. PAPeter Attia2:10:12

        Quick question. Did the triglycerides go up or stay the same? And I'm-

    30. EWDr. Ethan Weiss2:10:15

        Serum?
13. 2:15:27 – 2:23:31

    Growth Hormone, Longevity, and Fasting

    1. PAPeter Attia2:15:27

       Now, if you block JAK2 and block the expression of CD36, do you eliminate the fat accumulation in the liver?

    2. EWDr. Ethan Weiss2:15:36

       Yeah. Yeah, that's the experiment we did. It wasn't 100%, but we basically brought it back down to almost, you know, to instead of it being 100 grams per milligram of tissue or something, it was like 20, uh, where a 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 two together and asked what would happen, basically, can you reduce the amount of lipid in the liver by knocking out both at the same time? And we did. And that experiment we did almost 10 years ago, and, and what was so fascinating about that experiment was we never intended to get into any of the insulin glucose homeostasis stuff at all. But when you're doing these experiments, they're expensive, and so we did a bunch of things, you know, measure-- We did, I think we did an insulin tolerance test for some reason on these mice. And we saw that the mice where we knocked out JAK2 just in the adipocytes had the most profound insulin sensitivity. Like, we actually killed our mice 'cause 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, they were super insulin sensitive.

    3. PAPeter Attia2:16:49

       And this was mostly glucose being disposed into the muscle?

    4. EWDr. Ethan Weiss2:16:53

       No. [chuckles] It turns out... So we thought that was interesting, so we then went on to kind of dig deeper on what was going on. Again, here we'd knocked out this pathway just in adipocytes, and we saw that if you knock out the pathway in adipocytes-

    5. PAPeter Attia2:17:05

       But I'm confused. So you knock out the pathway in, in adipocytes. When they're hypoglycemic-

    6. EWDr. Ethan Weiss2:17:10

       Right

    7. PAPeter Attia2:17:11

       ... you're putting that glucose-

    8. EWDr. Ethan Weiss2:17:12

       Right

    9. PAPeter Attia2:17:12

       ... very easily into muscle or into liver. I mean-

    10. EWDr. Ethan Weiss2:17:15

        Right

    11. PAPeter Attia2:17:15

        ... 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, um, fat cell, right?

    12. EWDr. Ethan Weiss2:17:21

        Yeah. So, 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, "Well, 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 we, 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.

    13. PAPeter Attia2:17:50

        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?

    14. EWDr. Ethan Weiss2:18:05

        It was within 30 minutes.

    15. PAPeter Attia2:18:07

        Oh my God.

    16. EWDr. Ethan Weiss2:18:08

        Yeah. Yeah. Yeah, it was really profound. And, and so this then sent us off on this, like, 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, it turned me onto the kind of remarkable figure, one of these figures in history that I didn't know before I got into this that I, I'm surprised you... This guy, Bernardo Houssay, who was an Argentine physician scientist who won the Nobel Prize.

    17. PAPeter Attia2:18:38

        First Latin American to win the Nobel Prize, right?

    18. EWDr. Ethan Weiss2:18:40

        I mean, this guy was unbelievable. I, 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, New England Journal of Medicine over five weeks. At one point, he had-- It was the most unbelievably [chuckles] productive period of time I've ever seen. And he ended up winning the Nobel Prize. He shared the Nobel Prize with the Coris of the Cori cycle, 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 'cause 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 where he took an animal and took the pituitary out and then gave the animal insulin and saw that the animal was-- He described it as they were more susceptible to being, to the toxic effects of insulin, so that they 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 th- those experiments continued on for 60 years and-

    19. PAPeter Attia2:19:57

        So let me just make sure I understood. Take away growth hormone and you're gonna become much more theoretically or appear insulin sensitive, but in reality, much more hypoglycemic.

    20. EWDr. Ethan Weiss2:20:08

        That's right.

    21. PAPeter Attia2:20:09

        Take away growth hormone in the absence of the pancreas, and you actually tolerate hyperglycemia better.

    22. EWDr. Ethan Weiss2:20:16

        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.

    23. PAPeter Attia2:20:25

        So severing the link between the hypothalamus and the pituitary?

    24. EWDr. Ethan Weiss2:20:28

        They were taking the pituitary out.

    25. PAPeter Attia2:20:28

        Were taking the pituitary right out.

    26. EWDr. Ethan Weiss2:20:30

        Yeah. Yeah.

    27. PAPeter Attia2:20:30

        Wow.

    28. EWDr. Ethan Weiss2:20:30

        And it was a very effective treatment, actually, except that it had significant morbidity and mortality of the surgery. So it's, it was-- At that time, they were, they had perfected the art of taking the pituitary out.

    29. PAPeter Attia2:20:40

        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.

    30. EWDr. Ethan Weiss2:20:52

        Yeah. The ultimate killer experiment happened in 1983-ish 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 sp- within a day spikes and stays up until they stop the GH injections, and it comes back down. And in fact, three out of the seven people in this one study got profoundly hypoglycemic when they stopped the growth hormone. So it turns out that there's a drug that blocks the growth hormone receptor that's used as a second-line treatment for acromegaly. It's called Somaver or Pegvisomant. 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, 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, as the effect. And for reasons that I don't understand, people just forgot about it. And so we set out to kind of try and understand, at least at the beginning, at a cellular level, how is this regulated, and we're trying to dig down. It turns out that it all comes back to your favorite molecule, mTOR, and it looks like it converges in this intersection between these two signaling pathways that evolved actually on-- I mean, growth hormone doesn't exist pre-teleost, so there's no growth hormone in an- in flies or worms. It's only in invertebrates and teleosts. And it co-evolved basically from insulin, which is not that surprising, right? IGF-1 is basically the target molecule of GH. It's not surprising that GH and insulin would have evolved in a similar way, even though they look very different, they act very different. So the way I think about it is that growth hormone's kind of retained a lot of the sort of metabolic effects of, 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, 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.

Episode duration: 2:54:10