The Peter Attia Drive - #134 - James O’Keefe, M.D.: Preventing cardiovascular disease and the risk of too much exercise.

Episode Date: October 26, 2020

James O’Keefe is a preventative cardiologist and bestselling author of The Forever Young Diet and Lifestyle. In this episode, James discusses cardiac physiology and what makes the human heart susceptible to disease. He provides evidence for what supports his approach to exercise--elucidating both positive and negative kinds of exercise for heart health. He also discusses the role of nutrition, specific nutrients, and pharmacological interventions to support heart and brain longevity.   We discuss: James’ background and why he favors a preventative approach to cardiology [3:15]; Understanding atherosclerosis and the misconception that it’s a “plumbing problem” [10:15]; The danger in excessive exercise—a reverse J-shaped mortality curve [21:15]; The story of Micah True—A case study of excessive exercise [49:15]; The best kinds of exercise for longevity—The Copenhagen City Heart Study [53:00]; Being a more balanced athlete and finding the right exercise intensity [58:45]; Heart rate during exercise, resting heart rate, and other important metrics [1:04:00]; Nutrition for cardiovascular health [1:09:45]; Important nutrients: Magnesium, potassium, calcium, sodium, and collagen [1:19:30]; SGLT2 inhibition for diabetes, cardio-protection, and general longevity [1:24:15]; GLP-1 agonists for weight loss and reducing cardiovascular risk [1:34:15]; Statins—Mechanism of action, safety, and useful alternatives [1:37:25]; A 40-year view on cardiovascular risk, and the possibility of reversing arterial calcification [1:45:45]; Evidence for high dose EPA and DHA for the reduction of cardiovascular disease risk [1:53:30]; The impact of omega-3, curcumin, and other compounds on mental health and dementia [1:59:00]; James’ focus beyond cardiology [2:02:15]; and More. Learn more: https://peterattiamd.com/ Show notes page for this episode: https://peterattiamd.com/JamesOKeefe  Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn

more now, head over to peteratia MD dot com forward slash subscribe. Now without further delay, here's today's episode. My guess this week is Dr. James O'Keefe. James is a cardiologist and medical director of the Charles and Barbara Dubok Cardio Health and Wellness Center at St. Luke's Mid-American Heart Institute, an enormous practice of more than 60 cardiologists in the middle of this lovely country. He is also a professor of medicine at the University of Missouri, Kansas City. James has authored best-selling cardiovascular books for health professionals, including the complete guide to EKGs, Dislippidemia Essentials, and Diabetes Essentials. James has also co-authored with his wife,

Joan, the best-selling consumer health book, The Forever Young Diet in Lifestyle. He has actively involved in patient care and research and has published numerous peer-reviewed articles, which honestly, I feel like I'm reading at least one every couple of weeks. I came across James for the first time about nine or ten years ago when I heard him speak at a conference, and frankly, what he had to talk about just threw me back on my heels.

And since that time, of course, we've become friends and James is in many ways a mentor to me with all things that pertain to preventative cardiology. In this episode, we talk about a lot of things, starting with his background and how he made the pivot from going into interventional cardiology to now this much broader area of preventative cardiology. We get into some really detailed, but very accessible physiology of what the heart does, how it works, and therefore how it's susceptible to disease. And then we kind of launch into some of the things I wanted to get to. I wanted to talk about the impact of exercise on the heart, both positive and negative.

We go into that in exceptional detail. We get into the role of nutrition and specific nutrients such as sodium, magnesium, et cetera. And then we round the discussion out with a sort of tour to forest discussion of many of the pharmacologic agents that some of you have probably heard of. And frankly, even, you know, this discussion taught me quite a bit and actually invigorated my knowledge for this space.

So I always enjoy talking with James and I suspect you will all enjoy this episode very much. So without further delay, please enjoy my conversation with Dr. James O'Keefe. James, thanks so much for sitting down with me today. I'll be not in the same physical location, which is always a shame. The last time we were in the same location, you swung by my office in New York, I remember it was probably about three years ago, and you were kind enough to bring a recent manuscript. You just published about the impact of exercise

on heart disease, and we had a lovely discussion. I don't think we had the time for a meal that day because it was an impromptu visit, but I never imagined it would be almost three years before we'd be doing our podcast, which is something that, from the moment I started a podcast, I knew I wanted to sit down and talk with you. You're also just an incredibly gracious guy

who's always sending me stuff. And so I consider you one of those people in as my sort of constant educators. So this is gonna be an exciting episode because I'm going to be learning a lot. And I know that anybody who cares about heart disease is going to be learning a lot. And I don't know how you cannot care about heart disease

if you care about longevity. Yeah, it's the heart of the matter for sure. And yeah, I think we all instinctively understand how important the heart is to our health. And I might say in the spirit of educating each other, I love your podcast. I think it is easily my favorite podcast. I love the way you dig down into the science

and really get to the heart of the matter without overhyping things. And I just think you're doing a wonderful public service for improving the health of the population. And the other thing I'm really impressed at because a lot of my fellows in residence and kids will talk to me about what they heard on Peter at TSO. Your audience is a particularly, if I might say,

tuned in intelligence, you know, interested in health and well-being. And I think you have a really, you have really curated a remarkable audience. Oh, thank you for that. I think you have a really curated, remarkable audience. Oh, thank you for that. You and I first met probably 11 years ago, I think. I heard you speaking at a conference

and it kind of blew my mind. You won't remember this because it's obviously a topic you've been speaking about a lot, but as the listener, when it's the first time I heard about it, it was kind of a gut punch. So it was probably 2011, and at that time, I was still a wannabe professional athlete. So even though I was into my late 30s, I still pretended that I was, you know, a professional something or other swimmer cyclist. Incredibly high volumes of training, incredible intensity of training.

Actually did the math for somebody yesterday, and I think I was probably on my bike at least, I don't know, 20 to 23 hours a week with, you know, a third of that being at or above threshold. And you presented data basically suggesting that that was harmful potentially. And then I may have actually gone too far, and I may have actually set myself up for cardiac injury later in life. So with that as a teaser, I now wanna take a step way back and talk about your journey to that among many other topics

that interest you. You trained as a cardiologist, and just for people who don't understand what that means, that means after medical school, you went and did internal medicine and after internal medicine, you then trained in cardiology. And then you went one step further and said, look, I want to do interventional cardiology. Can you tell people what interventional cardiology is? Yeah, so that's using procedures to fix the hard, whether it's putting stents in the corner arteries or putting in pacemakers. These days it's expanded to fixing the vows. The technology is

just absolutely spectacular these days. We can put in vows. We it's become our default way of replacing valves now is through the artery. So, it's a really cool field. At the time, I went, I trained at the Mayo Clinic for internal medicine and cardiology and then went down to Kansas City at the Mid-Americ Heart Institute in 1988 to work with Jeffrey Hartzler, who was the world's expert in interventional cardiology He invented in fart angioplasty that is somebody's having a heart attack

He had the soda hutspot to you know go in do an angiogram figure out which vessel was blocked open it up with a balloon And suddenly the pain goes away at the time it was radical. This is 1980 and he took a lot of heat for that National at the meetings, but it turned out you know to be a game-changing therapy announced that it's the standard across the world for you know for treating an eclaustic cell. I went there and worked with him and started off my career and and maybe I'll back up saying You know, I'm like you. I love exercise. It's how I call myself down I'm like you, I love exercise. It's how I call myself down, turn myself up, whatever. I mean, it's just always, my kids say it's been self-medicating, I'm a hyperactivity all my life. And there's probably some truth to that. And it turns out that exercise is good for ADHD.

Never had trouble focusing. But certainly exercise, since I was a little kid, is just my mother used to her mantra to us was up in the prairie up in Northern North Dakota near Canada, which said, you kids, go outside and play. Go play with your friends outside. And so that was kind of what I did growing up. And I got into basketball and running cross country in high school when I was just fascinated by heart. So I figured out I wanted to be a cardiologist when I was 13 or 14 just because I was fascinated

with the heart. So back to, you know, through my cardiology training and then doing interventional cardiology, and I did it for about a year or two and then I realized this is back in the night, then we're only doing balloon angioposties. So we balloon these dialy, you know, dialy these vessels up in elective people, we're having angina. And then they'd be back in six months or a year with more blockages.

And just don't I mean, this is not the idea of way to treat cornea disease. This is a systemic disease. It's highly modifiable. We just need to, you know, focus double down on prevention. And this was just when, you know, prevention was blossoming, you know, statins came along in 86. And, you know, we're, you know, prevention was blossoming, you know, statins came along in 86, and, you know, we're, you know, the beta blockers. And now, I mean,

it's discontinued to blossom. So that coronary disease these days, you know, it's the leading killer in America should be an entirely preventable, medically managed disease, unless you have an MI. You don't need to be going in having procedures, stands in electively. We have the tools. And so it's also just the more enlightened approach. I mean, it doesn't pay well. You don't get paid for prevention,

but it is the logical way to approach disease, whether you're a physician or just a person out there who's trying to live a happy, long, fully functional life. I mean, you want to be thinking proactive, and it is so effective. We know what works now, but we just have to kind of get people's attention and get them to change their habits lots of times. There's a lot in there, James, so let's kind of go back and hash some of it out. So the first thing you noted was that in its earliest renditions as a specialty, interventional

cardiology, basically had one tool, which was balloon angioplasty. And so as you explain, you're putting a very small catheter. Can you tell somebody how large a coronary artery is just to give them some scale? So let's take the left main artery, coming right off the aorta, right before it bifurcates into the LED in the CERC, right at that Widow Maker location, which is named appropriately. How many millimeters is that in a normal, healthy, 40 or 50-year-old? So, that's typically about four millimeters, four or five millimeters, the left man cornering, you know, so not quite half a centimeter, which is a third of an inch. Yeah, so we're talking tiny, tiny little, little thing.

Yeah, it was even smaller than that. It's probably even, because an inch is 25.4 millimeters for context. So it's four is obviously less than a quarter of that. You put a little catheter that's obviously smaller than that into said vessel, and that catheter is complicated enough in that it has a built-in balloon that the operator outside the body can control with a syringe by inflating it or deflating it as needed with saline. So it's a really brute force method, isn't it? To sort of force open something that's narrowing. And of course, at the time, you weren't leaving anything behind.

So the best you could do was get in there, inject saline back and forth, basically use the hydraulic pressure of that to try to force open what was going on. And then you left. Now, years later, obviously, interventional cardiitis could leave behind something called Stents, so little flexible metallic things that would spring open and stay open. And then there's been an entire evolution of that. So folks who are interested, I had a great discussion on this topic with Ethan Weiss. If you're interested, check that podcast out.

I don't recall which episode number it was, but if you just search Ethan Weiss' name, it'll come up. And we go through the history of this a little bit, but more importantly, something you alluded to, which is kind of what the literature tells us about it, which is outside of a few settings. One of them being someone who is actively having a heart attack, even today it's not clear there's an overwhelming benefit to putting these stensen people. There's certainly a lot of economic benefit to certain parties, but there's not an enormous clinical benefit outside of a cute MI and we can bifurcate into which types of MI, etc. But, you know, for someone who shows up asymptomatically with a blockage, I don't think there's

a single shred of benefit unless something has changed in the literature in the last few months that I was unaware of. Is that still true? That's absolutely true. You know, we think of this, and it's very logical, which is why it's been, what are the many reasons why this has been so difficult to extinguish this flawed paradigm, that this is a plumbing issue. You have blockages in your arteries. Well, duh, you get rid of the clog. That's that simple. So we've been working on that flawed paradigm for 40 years now. And you're right, as logical as that is, it doesn't really turn out to be true. If you have an acute coronary syndrome,

but the way to think about atherosclerosis is kind of like the zits we get when we're teenagers, and we get these postules filled with oxidized triglycerides and LDL cholesterol, then then attract the monocytes and the macrophages that elute these inflammatory markers and they thin out the collagen overlying the zit and the ruptures and, you know, and it drains and heals. If it's a particularly bad zit, you end up with an acne scar

for the rest of your life. That same thing happens in your arteries underneath the skin of the artery, the inside skin, which is the endothelium, you form these zits. These postural filled with nasty yellowish and flamed and these they get hot, they rupture and instead of just draining, they attract thrombide because they think there's a rent, a hole in the vessel. So a thrombus forms with platelets and fibrenegin. And over time, you know, it heals if you're lucky enough. And mostly, most of the time you are, this happens a time,

a time again, through decades before it gets the point where one ruptures and then completely closes it off. But in the meanwhile, every time you get one of those inflating zits, the ruptures, you get the growth factor, stimulate the growth of the smooth muscle in the collagen, and if it's a really bad zet, you know, eventually you'll calcify. And those are fossil evidence of previous badly inflamed zets, if you would. So this is like really everyday common stuff, but we know how to prevent it, but going in with a balloon and addressing one layer and by the way tearing it up even worse,

it works if you're having a heart attack, but most of the times we can, we can regress those plaques, we can melt the inflammation out of there with a lot of things we can talk about, died, lifestyle and exercise, keeping the lipids down, and the triglycerides down.

And we can't make the acne scars go away. They're there forever once you have those calcium deposits. But we can pretty much make the risk go away. And that's why prevention is just so effective and so instrumental. Well, again, I think you said a lot there. And I want to go back because first of all, I love that analogy. I've never thought of using acne as an analogy. And I think that's actually a more accessible analogy than the ones that I use. So I think with everybody listening to this,

I'm going to declare that I'm going to start plagiarizing that. I hope you don't mind. What I find interesting, and I think it's important for patients to understand this, is the complicated biology of both the oxidative piece, the inflammatory piece, and how they feed off each other. And it is a bit of an irony, isn't it? That the body is actually trying to repair something.

The immune cells, when those monocytes get recruited to the site of endothelial injury, and obviously when they translocate and through the endothelium and become macrophages and start doing everything that you just described, which leads to this creation of thrombus, we would normally welcome that response elsewhere in our body, right? If you were out in the field and you got cut, that's exactly what you would want to happen. You would want the immune cells to show up there to make sure there are no bacteria, and

then you would want those thrombocels to come and prevent you from bleeding. And so the problem is all of that stuff is happening in an area where you don't have a lot of real estate. You've got a few millimeters. And that's why it can obviously lead to this enormous problem. The other thing you said that I think is it just can't be overstated is the understanding of what calcification means in that context. I had a patient I saw this week

who after some hesitation finally agreed to have a calcium scan. He had very elevated lipids for a number of years but they seemed to elevate more in the previous few years. He had been quite resistant to any medical management of that. And frankly, his other factors are really good. So, this is a guy who eats very well, who exercises very well, is metabolically very healthy. So, when he got the calcium score, you know, it was about a hundred and change, placing him between about the 75th and 90th percentile

for age, located in three vessels. He was not visibly alarmed, right? He said, this is really bad. And, you know, the stenoses in each of these bicalsification were, you know, in the ballpark of 30 to 50 percent. And what I tried, and I don't know if I explained it successfully enough to him, was, look,

the 30 to 50% stenosis you have in that vessel is not the issue. That's a huge warning sign of what has been going on over the past decade. It's telling us that now is the time to act and add other agents to our toolkit for how we're going to prevent myocardial death. The analogy I use is it's like having bars on the window of a home. You know, it doesn't tell you that there's a break in that it's about to happen. It tells you that you live in a very bad neighborhood and there's probably a break in that took place at some point.

Yeah, it's a great way to put it. And also, I'm glad that, and I know from our previous conversations that you're a fan of the calcium score, we call it Cardio scan, we charge $50 for it, we use modern CT, high speed CT scans that give these really great pictures of the coronaries with a minimal dose of radiation. So man over age 40, women over age age 60 I call it like the mammogram for the heart. I mean everybody should have one really because you can have a lot of risk factors for like say lung cancer. You might be a smoker and a family history and

this is that the next thing. But if we do a scan and see that you're growing a tumor, that's a whole different deal. And that's the way this is as she point out, there's a lot of people who have high cholesterol and high blood pressure, bad family history, just a frightening array of risk factors. You do a calcium squadron and it's zero. And you say, well, you've gotten through 53 years of life without making any hard plaques. So we're not going to like, we maybe don't need to use a statin on you. Maybe we don't.

Maybe we can tolerate it. It seems like you're doing fine. On the other hand, there's a lot of people who have relatively minor risk factors start growing plaque. And let's be clear, your coronaries should be soft and supple and smooth, like they were like when you're a baby, when you're a teenager. There's no calcium in the coronaries normally. And you see people, I think the record I've seen is 13,500 per calcium score. I mean, I often show the residents

like who put the Houndspeild area of interest over the left main of the LAD, and it'll be 800 and 900. Then you go to their spine. And it's 600, 700. Their arteries are more bony than their bones. That's not a good thing. What is the youngest person, James, that you've seen a legitimate spec of calcium in? So something that's not an artifact of a score of one or something, but where there's actual calcification? Yeah, late teens, but that's really unusual. 20s, you start seeing it.

And I might say that family history, when people come in like the patient you describe the coming to see, well, why do I have this? I'm doing everything right. They said, well, you probably have a bad family history, right? Yeah, yeah, I do say, well, if you weren't doing everything right, if you were a smoker, you'd probably already have had a heart attack, you know? So some of this is non-modifiable,

but more and more. I mean, this is a highly modified other process. Gosh, I almost don't know where to start, but I now feel like I want to start talking about some of the exercise stuff. So let's, I want to come back to cardiovascular disease prevention, because there's so much I want to talk with you about, with respect to glycemic control, hyperinsulinemia, other agents that we should be thinking about beyond just lipid lowering agents. And we can dip into that, but I want to talk specifically about one of my favorite classes

of drugs, SGLT2 inhibitors. But before we do that, let's go back to circa 2011. James O'Keefe is up on stage and he puts this graph up of a J-shaped mortality curve or exercise. Can you? And by the way, at this point, Peter Atia, sitting in the audience has probably just finished up of a J-shaped mortality curve of exercise. And by the way, at this point, Peter Atia, sitting in the audience, has probably just finished a four-hour bike ride. And he's proud of the fact that he kept his heart rate above 172 for half of that time.

Can you walk people through basically, not that you remember that exact talk, but basically the thesis. It's a reverse J curve, actually, because if exercise were a drug, it would be the best drug we have for preventing heart disease. I mean, for that matter, for preventing dementia, preventing osteoporosis, depression, diabetes, obesity. I mean, it is a wonder drug, if it were a drug. But like with any drug, you gotta get the dose right. Say you're using Carvedal All, one of my favorite drugs. And you give somebody who has a favorite,

or recent in far, or high blood pressure, you give them Carvedal All, but it's one milligram. You don't get any benefit, right? On the other hand, you give them 120 milligrams twice a day. So, if you give them 100 milligrams twice a day of carpet alone, it's a disaster. I mean, the blupper is going to be low, they'll feel terrible. I mean, they'd have a hard time getting up off the couch. Exactly, right. So, it's kind of the same thing with exercise, and amazingly, the dose of exercise to get benefit is really small. I mean, most 50% of Americans do no exercise.

If they just got off the couch and went for a walk, a breast walk, 15 minutes a day, they would get like a 30% reduction in serious cardiovascular disease, 15 minutes a day. Ideally, we say 150 minutes a week is a lower limit benefit. The point is that early, steep limb of the survival perverse exercise does fall steeply. Your benefit goes down 30, 40, 50 percent. But then for the last uptick, the people doing the most extreme versus the exercise, you start to lose some benefit. And it's probably upwards of a third of the benefit. So people argue, well, I mean, no sense scaring people off of exercise. I mean, it's just sort of an encouragement to not exercise knowing that if you're overdo it, you could make yourself worse.

And to be clear, it's only like 2.5% of Americans are probably overdoing exercise, versus at least 50% who are underdoing exercise. But still, it's a bit like just because 50 to, well, 70% of Americans are overweight or obese. And it's like saying, well, we don't really want to talk about the dangers of anorexia because then, you know, we're kind of With so discouraged people from not eating as much. I mean, it's the mere image of this but the point is you can overdo exercise and you know, it might be interesting as just an example I know that you swam the cattle, you know, channel like 15 years ago, right? Yeah And I mean, that was pretty amazing feat. So when you're sitting here talking to me

and your heart is beating probably about 45 beats a minute and pumping out about five, lose a minute of blood. When you're doing high intensity intervals or when you're swimming across the channel, that, you know, I mean, fast, great. You did that 20 miles and like 12, I mean, 10 and a half hours. So actually, I think cycling is an even more amazing place to show that, because actually,

for the channel, I would probably, A, there's something about swimming where you're horizontal. I think your heart rate for very short distances can obviously climb like crazy, but I find on the bike, you would get the highest heart rate. So for me, the maximum area under the curve heart rate was a one hour time trial. So like a 40 kilometer time trial would be absolutely maximum heart rate. How fast would it be going? I have a slow heart rate all round. So my heart rate would be about 172

for that type of a race. For an hour. Well, take the lesson an hour probably. Yes, exactly. It would take about 56 minutes, 55 minutes maybe. No, that's a perfect example because it's not only high heart rate, but it's exercising under a load. It's like rowing, you know, this is your, you're using big muscles, you know, your blood pressure is also probably 200. Your systolic pressure, your pulmonary pressure is probably 80,

67, 80 more minutes. Let's give people some metrics of normal. So for obviously doctors listening to this, we'll know what we're talking about, but let's take a step back. So let's say my blood pressure is, I've pretty normal blood pressure. I'm probably about a 115 over 75, is my normal blood pressure. Can you tell people what that means, by the way?

What do those numbers mean when you have a blood pressure checked? You know, this is just the pressure that is exerted to pump the five liters of blood around your circuit every minute. It takes that pressure to, you know, that's the normal pressure to just kind of get that blood squirting around there. And then it comes back at only like two or three or four more, but it's just murky up from the legs.

And that's a more difficult physics problem, right? Because you're over kind of gravity at low pressures, which is why it's good not to be obese, and it's good to be exercising, because those muscles milk the blood back through the veins, through the valves, up to the heart. And those two numbers, of course, referred to as systolic and diastolic. The systolic is when the heart is squeezing. So during the squeeze of the left ventricle, the pressure at the tip of the, basically in the aorta, is 115 millimeters of mercury. Now, anybody who's ever mucked around with a pressure transducer will actually be surprised at how much

pressure that is. That's a non-trivial amount of pressure. If you've had the luxury of operating on people, you know what a hundred and fifteen, even a normal hundred and fifteen millimeters of mercury, that'll squirt across the room. Across the room. But the 75 refers to the relaxation phase of the heart. It says even when the heart is relaxed and in the what we call diastolic phase, receiving its blood supply, there's still quite a bit of pressure in there. 75 millimeters of mercury in my case. Because your vessels are nice and elastic. So you know, receives the bolus of blood, everything expands. And then when the air develops shots, then those vessels, they rebound a little bit and they keep the, take this sort of pulse-tower

bolus flow, and turn it to more of a laminar, less bowl is flow. So that elasticity of the vessels are super important. Now you talked about my pulmonary pressures. What are my pulmonary pressures sitting here right now? And I'll confess to you, I have no pulmonary disease, though I've never had a swan ginsengath that are placed in me. So what would you assume my pulmonary pressures are? Oh, they'd be low, you know, like 20, 25 or 15, something like that, nice and low. Okay. So basically, that's the same exercise, but now you're in my pulmonary

arteries instead of my systemic arteries. Let's just assert that my heart rates 45 beats per minute. And you said my cardiac output is five liters per minute. So that means every minute, my heart sends five liters of blood around my body. So I love that you brought up cardiac output because I think that's the variable most people are sort of failing to appreciate how much that has to improve. So when a weekend warrior like me would try to do his best one hour time trial or when the best cyclist in the world or the best runner in the world is, you know, doing their most exerted thing.

What's the variability or the range in cardiac output that we can see from best in the world to sort of weekend warrior to average condition person. Just by way of context, if you look down at your hand and make a fist, that's about how big your heart is. This is an amazing pump. So five quarts a minute, think if you were squeezing a bowl, five quarts a minute. Five liters per minute. Yep. Five liters per minute. It never stops. And you're a good heart should have It never stops and you're a good heart should have About three or four billion beats in it Without ever stopping, okay, it's about a billion beats every 30 years Which is for a math geek like you it's kind of fun to think about you know, you know think about

Designing a lifestyle on exercise program to sort of minimize number number of heartbeats per year. Okay? And it does involve exercise, but it doesn't involve, you know, it doesn't involve perculean efforts of protractive exercise. All right? But a good athlete like you, an exceptional athlete like you, you go out and do that time trial, that one hour time trial, that 175 beats a minute under load for an hour. You're pumping like 30 or 35 liters a minute. Think about that. You know, 10 gallons a minute. You know, like lands are Armstrong and those, you know, the professional cyclists or cross-country skiers will get up to 40,

40 liters per minute. You mistakenly referred to me as an exceptional athlete, which even at the time I wasn't, but yeah, when you do talk about the exceptional, when you talk about Lance Armstrong riding up Alp Duets in 38 minutes, and it doesn't matter that he was on EPO. It really doesn't change the metrics of this. 40 liters per minute of cardiac output. You know, to put this in perspective, James,

I just love this so much, because the only times I've ever measured cardiac output are in patients in an ICU. I mean, I can't count the number of times I've put a catheter into somebody's lungs to measure and their heart to measure their cardiac output, but it's always been in the setting of a patient under critical care.

And in that setting, it would be routine to see two and three leaders of cardiac output per minute, and that's with every drug under the sun used to squeeze their heart, and to think that you and I have the luxury of sitting here without a single drug to increase the contractility of our heart and we're at five liters per minute. And even a couple of old guys like us could probably go out and exercise and still hit 25 liters per minute. But that the best in the world can hit 40 liters per minute. Now, let's do some math.

To get to that volume flow rate, really, their heart rate isn't making up the whole gap because cardiac output is a product of two variables. The heart rate and the stroke volume, can you sort of explain how those play together? Well, the stroke volume is, you know, your heart's a pump and so, you know, in between beats it fills. So how big it can accommodate, how much volume it can accommodate with each beat is an important factor. And I remember Miguel Indirene had some studies done years ago

and his heart was basically twice normal size. So you get the heart rate up, the volume goes up, your arterials and venus dilate up so that the resistance goes down. And the heart is actually not just a pump But it like it rings out the block. It's shortens and twists and when it's going fast and your exercise And it's basically sucking blood out of the lungs and the venous system into this and pumping out as fast as it can I mean, it's just it's just an elegant astoundingly well-designed system when it's used right and of course that's one of the beauties of exercise

You know you can feel them from you as you get into shape you can just feel yourself being more capable of this and it's just It's just intoxicating and it's one of the beauties why people get addicted to exercise but but the point is To get back to the underlying concept is that you could imagine to get back to the underlying concept is that you could imagine when you're going that hard and your blood pressure is up and your pulmonary pressure is up and you're doing 25 liters a minute, the soft, pliable chambers in the heart, that's the atria, the right and left atria, and the right ventricle, they get distended, they stretch out. Let's pause on that so people see why James, because if my cardiac output, which is the dot product of heart rate and stroke volume, meaning if one goes up by twofold, the other

can go down by half and they'd stay the same. But if the whole thing has to go up by six X and my heart rate's only going up by 3x because 45 to 170 is about 3x. You have to bring the other one up by 2x. So how do you take up stroke volume that much? Well, part of it is what you just said. You can squeeze harder, you can twist, you can get every last dropout, but there's no getting around what you're just about to explain to people, which is you have to make that chamber a heck of a lot bigger.

Right. And, you know, we're designed for this through nature. We're designed to be very active creatures, but, you know, most of the time, if you look at tribes in the wild, they're doing like 16 or 18,000 steps a day, but most of that is out of sort of a comfortable walking pace. Lots of times they're carrying things or they might be lifting, chopping, winning, whatever, building.

And occasionally, critical times in the hunt or whatever, they might be sprinting. Although the younger members in the tribe would be assigned that task because they're fast or runners. But we're not really designed to do what you did when you were doing these like you still do. We'll do these really long bike rides, the chambers or marathons, ultra marathons, you know, the chambers dilate up and we have enough circulating buffers in our

bloodstream because this is like an engine, like an excursion muscle uses fuel, glucose, fatty acids, ketones to create energy, but it throws off exhaust. And when your excursion is in that hard, it throws off a lot of exhaust in the form of free radicals. We have a lot of circulating buffers in there to basically neutralize those free radicals, but we deplete that after 45 to 50 minutes of high intensity exercise. And there's good animal studies showing and human studies showing that diastolic function improves for the first 30 minutes of exercise and by 50 minutes or

60 minutes, it starts to worsen. And the endothelial function will start to worsen to after you depleted those antioxidants after 45 or 50 minutes, you start like searing inside of your vessels. Those endothelial sensitive endothelial linings with high, high free radical levels. And you also start overtaxing the heart muscle. And I want to say it's not a big deal, especially when you're young. Youth is, you know, when we're young, we're so resilient.

That you can get away with doing this stuff when you're 15 or 20 is, you know, when we're young, we're so resilient that you can get away with doing this stuff when you're 15 or 20 or 25 or 30 or 35. And maybe even 45 or 45, after 45, it starts more likely taking a toll. You start seeing, you know, triponans will rise and NT, Pro and P will rise after really, really strong efforts

like a marathon. Tell folks what those markers mean because anybody who's been to an ER with chest pain will know what a trapponin is or has taken their grandmother into the ER with heart failure. But for most people, they might not know what those are and why seeing an elevation in those post exercise should cause us to pause. Yeah, so trapponin is one of the proteins that is unique to the heart. And it leaks out of the heart and gets into the bloodstream when there's been some heart damage.

We usually associate it with, like you say, heart attacks where the artery closes off and the muscle is started for oxygen and it dies downstream unless there's good collateral. So that really raises our eyebrows and gets us into action when we see an elevated tropone. But a lot of people, I mean upwards of half or more, people after a marathon will have an elevated tropone.

It's just at that high level, 25, 30 liters a minute for two and a half, three, four hours. It starts over stretching the muscles in the atria and the right ventricle particularly, and it leaks into the bloodstream and Again, you know like it tell people if you want to run a marathon fine, you know run one or two But don't make it you know, it's like like like climbing Mount Everest You know if you want to do that do it once but don't do it like three times a year You know you could do it brag about it and all that but this you know You got to move on to healthier forms of exercise because these, really, especially after

age 40 or 45, really protracted exercise will cause this small little micro damage, like overstretching and tearing because the high levels of cataclysmines and high levels of free radicals that are now unbuffered. If you're designing, like I like to talk about training for longevity, it's very different than training for peak exercise and a car buff like you can understand that's like if you're going to build a Formula 1 car to go fast, powerful, the most impressive performance machine ever, it's going to look and perform a certain way and it's good at that. But it's not going to go 500,000 miles. It's built for power and speed and performance now.

Like a car that's going to go 500,000 miles, I don't know, it might be a Honda Corridor that you're driving never more than 70 miles an hour and you're maintaining it really well. The point is that you have to really focus on what your goals are and our goals as an athlete is different than our goals for longevity and health and well-being. You know, I love that analogy and I appreciate you using it for me because you know how much I do love cars. In fact, I actually think I made that comment to a patient this week using a Formula One car as the reference, because as you pointed out, James, these are cars that are built for each race effectively.

They'll go through three engines in a season. So everything about that is meant to extract the absolute maximum performance. Again, I wanna reiterate what you said. If your goal is to win the Iron Man triathlon, nothing we're saying here should pertain to you. We're not going to tell you how to train for that. That is a remarkable feat. I mean, when I think about what it would take to go seven hours in that heat to do what's involved in an Iron Man, I can't fathom that. There's never a time in my life when I've even approached the level of raw performance

that the winner of Iron Man is going to take, or frankly, even somebody who comes in under 10 hours. But swimming the Catalina channel in the Dahlhurt, you know, in 10 and a half hours that is also a pretty remarkable feat that's way beyond what normal person's anywhere capable of doing. Yeah, perhaps. I've never had to do all three at once. So when I was growing up, I was a good runner, good as maybe a stretch. I was a decent long, long, long distance runner.

When I was swimming channels, I could swim for long distances and then when I could time trial, I could time trial. But there's something about the Iron Man or triathletes that can do all of those things simultaneously that's always impressed me. But my point is you're bringing up the important distinction here, which is at some point an individual has to decide which master they're serving. Are they serving the performance master? Are they serving the longevity master?

And I think everybody goes through a difficult transition here and I see this struggle with many of my patients, especially the former exceptional athletes, or frankly not even people who were themselves exceptional athletes, but people who have also become, I don't know how to describe it, but they've found a new sense of purpose through some of their athletic endeavors. And they've done their first marathon and they've thought, oh my god, this is really a great thing to do because there was a purpose, there was a goal, there was a training plan, there was a camaraderie that came through that. I got to do the thing, and now I want to do it again and again and again and again. And they've made a lot of friends doing it too, and it's a bonding experience and there's a lot good about that

But I'll just interject my my transition is because I can't have played basketball, you know competitively in varsity in high school and college and then For the first two years of college anyway, and then because I felt that that exercise was so important I made this mental note when I stopped playing varsity basketball that other exercise pretty much every day because I knew it made me happy and healthy So then I kind of got into running, then triathlons, and I did short, you know, short distance sprint triathlons, but I hammered it. I mean it trained really hard And especially during my 30s up until my mid 40s, and I was pretty good, you know, winning likeink distances, you know, and local races and stuff like that But it was just the fun of the competition and the friends and all that But then then I started noticing when I'd go out and I also on the back of my mind being a cardiologist You know sort of thinking being proud and happy that you know the capable of doing this, you know in my in middle age

But then I started noticing like when I'd go on really hard rides and do those hard intervals, after I have this sort of vague sense of like aching in my chest and sometimes I feel some, like I'm one of those people, maybe you are too a lot of people who are athletic, you can feel like if I stop right now and be quiet, I could count my pulse just feeling every heartbeat. And I could feel some at-to-be, some PVC's or some PACs or two or three runs in a row of PACs or as super ventricular tech, Cardi and I thought, you know what, my heart is not happy about this, you know, and it disturbed me a little bit and I kind of checked Cardiostan, had a little bit of calcium, 21. But then I started thought about it and thought, you know, this is next no sense.

I mean, I'm thinking that if some exercise is good and moderate exercise is better, that extreme exercise is the best. There's nothing in biology like that, where the far extreme, it's usually moderation, and especially moderation in the context of what we are evolutionarily designed to do. And what I was doing for a 45 year old

was out of bounds with respect to what, you know, my body was expecting. And so I started looking into this and talking to some of my friends and colleagues from around, well, my practice and around the world really Peter Schnor and Copenhagen putting the episode on databases and showing that in fact, and this is there in plain sight all the time, by the way, a path in Margaret, one of the Godfather's of the exercise movement in his study in the New England Journal of Medicine pointing out in these Harvard alums that exercise improved longevity like eight to ten years. But in the extreme death size, it's just a small group of people who are doing the most

exercise per week actually lost like 38% of the benefit conferred by the less extreme effort. And then Ken Cooper, another one of the sort of founding fathers of the modern aerobics movement down in Dallas, used to say, if you're running more than 15 miles a week, you're doing it for some other reason besides health. So they recognized, and even apocrates, 2500 years ago, said, if we could prescribe the right dose of exercise and nutrition, not too little, not too much, is the safest way to health.

I mean, so this has been there right along that, you know, even back 25, 500 years ago, they recognized that it's not going to be centering, but you can overdo it. You can kill yourself with too much exercise. Let's go back to what you were talking about with respect to PVCs. Explain to folks what's actually happening with a PVC because I think this for me became the area where I started to pay attention. Just to be clear, James, it took me three years to fully embrace this message. It was not until 2014 that I finally realized

I needed to get into one camp and I couldn't serve two masters and my higher priority was gonna be my longevity. And that meant I was not going to do these crushing workouts anymore. My workouts were going to be geared towards what makes me live longer. And the data that I found most convincing were the electrophysiologic data. So it was looking at athletes, the incidence of atrial fibrillation in cyclists and runners who were at or above a certain volume versus normal age-matched controls. And yes, that's full of all the same problems and pitfalls that epidemiology was full of.

But when the magnitude was so big, it was difficult to ignore. And if I recall, the magnitude was in the ballpark of about 7x. In other words, if you took, you know, retired professional cyclists and you compared them to aged matched controls, it matched them in any way possible. These professional cyclists were seven times more likely to have atrial fibrillation. Does that, is my memory serving me correctly or am I out to lunch on that? No, that's almost spot on. But also I point out that, you know, the heart is very capable of healing itself, almost always.

And so, it's really these high volume athletes, high volume high intensity athletes who continue to do it. All right, past, you know, like in the middle of age and beyond other ones, I see these people all the time because I've written about this a lot as patients all the time come in with a fib, and it's like 700% increased incidence of a fib, which is a really common heart arrhythmia where the atrial where the rhythm arises becomes disorganized and chaotic. And so it just scutes through the AV nodes into the conduction system down in the bottom, working part of the heart rapidly and irregularly. And it's becoming more common all the time

in America because it's common among older people, obesity, diabetes, sleep apnea, tall people, too much alcohol can cause it. But one of the causes that we see is in people who are overdoing high intensity exercise. So yeah, you're right on there. I cut you off or rambled too long in my question, but tell people what a PVC is and why and is that an early warning sign. The high cataclysmine levels from protracted exercise and the high oxidative stress and

the stretched chamber causes some tearing of the myocardial fibers with protracted exercise. And over time, that can cause a little micro-islands of fibrosis in the mycardia scar tissue. And so if you keep doing this like year after year, decade after decade, you start ending up with this stiff dilated chambers, which then is the electrical milieu that is favorable for creating these rhythm problems at first things like PVCs, but eventually can lead to VT. But again, NA5 is much more common still, but these are signs that your heart's irritable. Your heart's been irritated by something,

and in this case, it's too much exercise. So let's talk about perhaps one of the more sad, publicly known examples of that, which you've spoken about publicly, which is the sudden death of Micah True. Tell folks a little bit about who he is and what a remarkable specimen he was, and what conclusions you drew from his death. Yeah, so he's sort of the poster boy for the thing, you know, that you've really kind of an extreme example. So Micah True was a remarkable endurance runner. The book, Born to Run, was written about him. And he was kind of a hippie who sort of dropped out of society and decided to just become

a runner. We went down to Northern Mexico and ran with this tribe that has his runners in it, the Tara Hamara Indians. And he would run just remarkable distances and became sort of like an example of any of this he was in his 40s or 50s when this happened but but he was out for a run and He died suddenly and they did an autopsy I'm going to found this you know dilated scarred up heart Just what we're describing you know the scarring in the atria and the ventricles especially the right ventricle

Interventricular septum. But the point is that he was really fat. He accomplished a lot of really impressive things, but it did take a toll on his heart. And now granted, he was doing just superhuman volumes. I mean, he'd typically run 12 miles a day, as I recall, and lots of times would do these 50 or 100 mile races through the desert heat, things like that. But, yeah, I'm not a big fan of these extreme, and there's more. I have a friend who did the seven marathons in seven days on seven continents, Meg. You know, she's a really, she's a good friend. I've known her for a long time.

She was one of the best triathletes in America when she was doing that 10 years ago. And now she still exercises a lot, though, she's kind of cut back on it. But if you measured what's going on with her heart during those times, it's not pretty. It's like the heart suffers when we really, really overdo it. Of course, all of these data that we look at, the inverted J curve, a lot of the Harvard prospective study, even other prospective, there's still epidemiologic. A critic of this would say, look, we don't have any randomized data, experimental human

randomized data, to tell us that the dose curve to exercise is non-linear. Again, what that means is, linear means the more you do the better you get. You're proposing, the more you do the better you get to a point, and then it actually goes down, hence the inverted or upside down J. What about animal models? Are there appropriate animal models that can be studied here, if so, what if they shown? Yeah, the animal models, most have done with mice, but a few with dogs, have been pretty much consistent with this, that you do see these elevations of a triponent acutely and if you keep keeping going for months or a year or two,

you can see these dilated chambers with the substrate for arrhythmias. And if you look at the epidemiological data in our last paper that we just published was called training for longevity, we put all the major 10 big epidemiologic studies and all but two of them showed this very distinct reverse j-curve so that you get this deep reduction in mortality, major 10 big epidemiologic studies and all but two of them showed this very distinct reverse j-curse, so that you get this deep reduction in mortality that the plateau is off in the middle and then at the very end, the fish hooks up. It's like diet and that so you're not going to be able to prove it because these are life

long kind of patterns that emerge and it's impossible to randomize people to it, but you know, there's a lot to be said for the end of one. You know, you pay close attention to your body. I can tell you for me as a cardiologist and also just as an athlete and a person, it was very apparent to me that if I didn't change this, it was not good for my heart. And let's just talk for a moment about

the best kind of exercise. If you just stop talking about volume and intensity, but just talk moment about the best kind of exercise if you just stop talking about volume and intensity But just talk about like the best kinds of exercise because this this friend of mine Peter Schnorr and Jacob Morat He's a he's a brilliant PhD from Denmark from Copenhagen Peter Schnorr founded the Copenhagen City Heart Study This is 10,000 Danes that they enrolled 25 to 40 years ago and focus kind of like the Franyhand study was in America for diet and lifestyle. This was like the Franyhand study for exercise. They sort of collected a lot of data about what people

were doing for exercise and then followed them through the decades. And you know, the people in Copenhagen, I think it's the city and the world that has the largest number of people who bike to work. I mean, it's just, it's a flat city. They have these, these have, this kind of really generous bike lanes and it's just really fun to watch how people bike to work. But they do a lot of other things.

And so they collect a data on eight or nine specific sports, including running, swimming, cycling, health club activities, which include treadmill and all those stationary exercise machines with, waiting to put it all together. And then there was tennis, badminton, soccer, golf, I think, for the ones. And so we sat down, we'd done some others analysis this data showing that was the moderat us runners that did the best for longevity during the four decades long follow up of that. But this was a more, this is a different look at it. And so we said, let's sport is best for conferring longevity. And so, you know, did all the multivariable analysis because, you know, tennis players are different than maybe cyclists or whatever.

But quantitative how much exercise per week, and maybe you know this data, but what do you think? I know it's just shocked me. I went over there to find a look at the data and we were sitting on a coffee table one Sunday after New and Heaven of Class I and talking it over. And he said, it reveals this data to me.

And I look at it, it's multi-variable, just data. And I was really speechless. I was just, it's multivariable, just data. And I was really like speechless. I was just, it just, just that, oh, what a waste we spent all this time and this is nonsense. So, what do you think came out as the least effective way for improving longevity compared to, say, sedentary population?

I've read this, so I'll let you disclose both the best and the worst to people. Okay, so the worst was health club activities and the best was tennis, followed closely by badminton, soccer, golf, and the middle three were like cycling, swimming, running. And that was like three to four years out of life expectancy, health club activities only one and a half year life expectancy added. And those social sports, Pat Mitten, tendus, golf. I mean, it's easy to imagine soccer, but we're like six to 10 years

added life expectancy, multivariable. And I just thought, well, it's not even a sense of publishing this, but then I started looking at it and thinking, wait, what if, what if it's not so much about what hammers your body into peak fitness as well as what sort of reduces stress makes you happy is something you can do lifelong and sort of fosters personal relationships because

there's a lot of studies in recent decades one by Julianne Lundstedt that said that single best predictor better than smoking or diabetes or exercise or blood pressure lipids for conferring longevity What's strong social support? You know relationships Or the key and you couldn't instinctively would understand that but then I start thinking well You know particularly for us sort of like emotionally challenged gender, you know males It's like we make friends at work, but and we have our family, but lots of times we bond by playing and When you think about these the sports

that were done playing Were the ones that conferred best longevity and and there also the ones that sort of promote more social activity So I think I think we need to change our mind around about what best exercise is not about if you're training for longevity, yeah, take it down a couple notches, but also make sure that you have some play in your life. We play this kids, we need to be playing as adults even more because it's so important not only for social bonding, for stress relief, for at the present, I mean, I just think it's so important. Yeah, I think my reading of that was basically,

look, there are a lot of variables that can't be teased out of any multivariate analysis or correction, but a couple of things stuck out to me. One was, I think you're right. I think what tennis and golf, badminton soccer offered that running cycling and swimming didn't to the same extent on average, not globally, but on average, is you got to combine two medicines instead

of one. And you know better than me that two drugs are often much better than one to control blood pressure. So when you got to combine exercise with social interaction, it does better than just exercise. That's sort of the first thing I take away from that. The second thing I take away from it, frankly, is the challenge of doing any sort of large-scale study where you don't have a close ability to understand the intervention.

And I'm very fortunate that I have a gym at home, so I don't work out in gyms anymore. But from the days when I used to work out in gyms, I realized that if we were going to treat everybody in that gym as one cohort of everybody who goes to the quote, health club, we would glean very little because the difference between what people did in that gym is so enormous that the average of that borders on meaningless, just as the average of what any group of individuals does is effectively meaningless

because there is no ability to control for it. So those are the two things that I took from that. Now, I do want to go back to kind of something you said because I look, I think there are going to be a lot of people who listen to this, who are going to be exercising more than what you put forth. I think you said earlier something to the effective look, 15 miles a week of running is probably adequate.

If running is something you enjoy doing, you probably don't need to be running more than 15 miles a week. I'll tell you this right now, my wife runs a hell of a lot more than 15 miles per week. So here's my argument to her to run less. It's an I use economic terms called opportunity cost. So, here's my argument to her to run less. It's an I use economic terms called opportunity cost. It's like, look Jill, I know you want to run 50 miles a week, and I know if you had all

the time in the world you'd run 50 miles a week. But it comes at the cost of you doing not a single other form of exercise. No strength training, no rowing, no this, no that. So really the argument is, and this was the argument for me in cycling as well, which was, look, one, you just, you're tired of spending all this time training when you, you have kids that are getting older and older and you have more kids and it's, there's just a cost to being away from that. But, but it really comes down to how can you be a more balanced athlete

for life? So maybe not a better athlete in a very specific sport, because cycling is a very specific sport, running is a very specific sport. If you want to be very good at those things, by definition, you're not going to be very good at much else. But life is a pretty complicated sport, and it requires strength, stability, aerobic fitness, and anaerobic fitness. Yeah, flexibility. I mean, all of these things. So you have to be able to train all of those things. And unless you're retired, I'm not sure how you'd want to run more than 15 miles a week if you have to be able to put effort into those other things. So for me, that is the prescriptive takeaway here is how do you have a portfolio approach

to exercise? What is your prescriptive approach to patients? That I just sort of laid out mine. Well, yeah, you're right on. As usual, if you're spending a lot of time saying running, I know a lot of patients who run, or cycle like a lot, I mean, 30, 40, 50 miles a week of running, and you know, like an hour or two a day of cycling, it's like, yeah, you're getting your aerobic fitness really high, but it's not great for your skeleton or your balance, I tell people just after 30 or 45 minutes of aerobic

exercise, if you want to do more, you know, circle back home and do some yoga, do some weights, these things that kind of don't necessarily tax your heart the same way that the other high intensity sports do, or sexual activity if nothing else is exercised that again is a totally different realm that is worth investing time and energy into and also, you know, is for relationship building and so yeah, I think that it's a matter of being more balanced and also if you if you try to figure out the area under the curve for, you know, maximizing your heartbeats, you want to do stuff that keeps your resting pulse low, but some high intensity intervals to keep your maximal rate, your maximal capabilities high. That'll develop fitness quicker than anything, some high intensity interval training,

in a relatively short period of time. But it's the sort of thing that high volumes are really high intensity exercise is just not I just don't think it's the ideal approach to fitness Even there's a podcast I did with Inigo San Milan where we talked very Specifically and in great detail about zone two zone two being defined as this area where you have the Maximum efficiency of the mitochondria so you're able to maximum efficiency of the mitochondria, so you're able to keep lactate systemically below two millimole and just barely keep it there, right? So you're sort of maximum utilization of glucose and fatty acid that is mitochondrial without undergoing non-oxfost. For most people, that's a lower level of activity than they're used to.

If you do popular classes, if you hop on a Peloton class or something, you're spending very little amount of time in that zone, you're spending, but you're also spending very little amount of time at peak capacity, sort of north of zone five. You're spending a lot of time in the middle, and I actually think it's that in the middle time that unless you're an athlete who competes in the middle, is actually some of the least important areas to be training. A lot of the data looking at even world-class athletes says,

it's 80% low intensity, 20% high intensity. Of course, their total volume is enormous, Of course, their total volume is enormous, but I think they even have the ratio right. And yet I think most people don't have that ratio correct. And they don't appreciate how important it is to do that low end aerobic, which depending on your fitness might just be brisk walking. If you're a little fitter, it might be, again, zone two level of fitness. One of the things, as a cardiologist, people are always asking me, you know, so what should my heart rate be?

You know, what's my training zone and a lot of stuff? And for most people, I tell them, you know, I wouldn't pay much attention to your heart rate. I mean, except for the fact that I love activity trackers and you know, that they could track the pulse and stuff, but I think the most important for amateurs about pulse are what's your resting pulses. You want to get that nice and long. We want heart rate variability. We want that to be more variable when you take slow deep breaths, which is why meditation or yoga is a really good thing

to add to somebody's fitness regimen. But with respect to time to you know get your heart rate maxed out, it's like there's a recent study showing in middle-aged adults looking at life expectancy as a function of number of steps taken. And people compared to people who were less than 4,000 steps a day, people who were getting 8,000 steps a day had a 50% reduction in mortality during 12 year follow-up. And people were getting up to 12,000 steps a day. That was a peak. I mean, the plateau there Above that it didn't go further, but there was a 67% reduction in mortality. So like you can get pretty much the full benefit of exercise with just a lot of of steps and most of those being walking. I would agree that you want to add some Some higher intensity interval, but it

doesn't take a lot. I mean, like, if you look at running, five miles a running week will give you the longevity boost from running. That's almost as good as it gets. One of the questions patients ask me, and I don't really know the answer I'm hoping you might, is how much resting heart rate is a function of fitness versus genetics. So sometimes because now a lot of our patients do use tracking devices and they often report

your lowest resting heart rate overnight, which would really be your true native. And I have some patients who say, gosh, you know, mine is 57. Why is it not 47? And I really don't know how much of that is their exercise versus, you know, look, some people just have different size engines that rev at different levels. For example, I've always had a very low heart rate.

So nowadays, my resting heart rate, my overnight resting heart rate, might be in the low 40s, but when I was athletic, when I was very fit, I would wake up with a resting heart rate in the mid 30s. So actually, I have a pretty high heart rate relative to my baseline now, but I've also never had a very high peak heart rate.

So I've just always thought of myself as having more of a diesel engine. I have to believe that's somewhat genetic. So what is your view around resting heart rate given that it is a metric people are becoming more and more aware of? So, for one thing, females tend to have higher heart rates than males, even at equivalent fitness levels. And that being said, resting pulse is a much stronger prediction, predictor of mortality, lower is better in that regard, lower pulse, better longevity in males than in females.

Males with a resting heart rate above 85 is not a good place to be. Some of it's genetic and as people get, you know, into advanced years, some of it's a disease, six-sided syndrome, you know, where your pulse just slows down because, you know, the engine's wearing out and they need a pacemaker. But most of the time, it's, you know, it's a function of, well, for instance, like alcohol, the more alcohol you drink, the higher your pulse will be, it's a function of, well, for instance, like alcohol, the more alcohol you drink, the higher your pulse will be, your resting pulse, stress, sleep problems, there's a lot of things, but it's generally a pretty good marker of fitness.

And so, like a lot of things, rather than worrying about how you compare to your body you work out with, is how you just compare yourself to you and keep track of your pulse and you'll notice that when you get into a rhythm like for instance, one of the reasons I love watching my resting heart rate and I'm kind of like you, I'm like it runs, you know, 42, 44 most nights and if I get over trained or under-slapped, I've been on call, been under more stress, and traveling too much. It'll start raining up to 47, 48, 49, and if you pay close attention to it and use that as feedback, it's a really great way to tune your lifestyle to get into a cardio-protective zone, and it involves the right amount of exercise and the right amount of sleep and not too much alcohol.

Plenty of downtime and play and no certain things. How much do you see patients resting heart rates improve with appropriate exercise based intervention? So when you take patients who are underdoing it, which as you said at the outset, we shouldn't lose sight of the fact. Most people are underdoing this drug called exercise, but patient shows up with the resting heart rate of 75, who's otherwise quite healthy, has a cac, their score is, places them at the 50th percentile, they're in no grave or acute danger at all,

but they say, Dr. O'Keefe, I'm here to get serious about this. I wanna, you know, I wanna bend the arc of my life, I'm 45 and this is the time to really pay attention, even though there's no heart attack in the next decade of my life at all. And you say, look, I want you to do X, Y, and Z. Is there an expectation that their resting heart rate is gonna be 55 one day?

55 only if they get really serious about, losing 30 pounds and getting fit from unfit. But more typically, 5 or 10 beats per minute is not uncommon. And you're happy with that? That's a positive sign to you. Absolutely. And of course, it goes along with their waistline coming down, and their blupper should come down, and their triglycerides lower, and their A1C lower.

So these things tend to move in tandem when you kind of dial in your lifestyle and diet and exercise program to that sort of ideal zone. Well, let's pivot then and talk a little bit about nutrition. Gosh, there are so many places to go on this, but something you've written extensively on is the relationship between diabetes and cardiovascular disease and what can be gleaned from that as a model

for studying a disease. So tell folks a little bit about that work. Well, this is another thing that I sort of paid attention to in my diet, and back when I was in medical school in the 80s and my training in the 80s. And how was the time when the predicate in diet and like a low fat diet was all the rage and unfortunately you know that took a long time to extinguish that but I started following that pretty closely and it was a disaster you know it's like my triglycerides went

from 80 to 300 and my HDL went down from 50 to 33 and I just thought you know I was getting skinnier and, you know, my athletic turns weren't better. And in fact, they were worse and I wasn't feeling like good. I thought, this is not the right diet. How restricted were you? Well, like for instance, when I, you know, I was at 20 something. You know, so I'd go out to eat with friends and we'd eat in pizza and I'd take off the

toppings and just eat the crust, you know. And then for a while then I kind of got into the keto phase and I would eat the toppings and throw away the crust, and then I figured, yeah, pizza probably just not. We're feeding at home. So, you know, and I'd eat lots of white rice and, you know, I'd try to minimize fat, and then I'd realize, you know, you can't generalize. For one thing that's a disaster for and it's played out on a population-wide level in America that kind of diet you know makes it's fat, belly fat, triglycerides, rub, diabetes, rates are up, it makes you hungry all the time, it is not the right diet. Just two days ago we published an article in our flagship cardiology journal in the world called the Journal of American Culture, cardiology called the Pesco Mediterranean diet intermittent fasting as like the omnivore's solution to the omnivore's dilemma of what to eat.

And we think if you put together like all the data and the guidelines and you know the observational data and a little bit of randomized data that we have that a diet that's moderately high in fat, very low in refined carbohydrates like almost no added sugar and minimal white refined grains, but high in nuts and extra virgin olive oil and high in fish and seafood and high in vegetables and low in processed food and drinking mostly water, tea, coffee, fasting for at least 12 hours, each 24-hour period of time, and preferably moving more like a 14 or 16-hour fast per day. We think this is arguably the healthiest cardiovascular diet, both for preventing diabetes

but also preventing heart disease and dementia, obesity, and a lot of the other scourges that are so common in our society. The Predamid study, which I'm sure I've discussed in great detail on a previous podcast, though, unfortunately, I can't recall. Hopefully, on the show notes, if it's been done, we'll make sure to link to it.

Probably one of the most impressive diet studies with respect to cardiovascular disease prevention. And, you know, I think the findings of that, though they needed a revision based on an error and randomization the first time around, were difficult to ignore when you consider the challenges of studying primary prevention, even with drugs, let alone with a diet. And yet to see the success of a Mediterranean diet in that study, that was a wake-up call for me. Peter, that is, in my opinion, the most important diet study that's been done. Emilio Ross was the primary investigator on that. He was a co-author on this recent paper that we've reloaked in the Muleon Eye, been working together on a lot of projects

recently, but it was the Mediterranean diet versus the American Heart Association died, which is the diet that we were just, you know, dissing the low fat, so trending towards vegetarian diet that's in high carbs. But that showed in this group of 7,500 people, followed for a four and a half years, that the primary endpoint, which was MI, heart attack, stroke, or cardiovascular death was reduced 30%. But also follow-up studies showed that the dementia, cognitive impairment, diabetes, obesity were also, each of those were significantly reduced in the people that got the Mediterranean diet. But it's important to point out that they were specific Mediterranean diets that half of

the people in the Mediterranean diet got a free liter of extra virgin olive oil per week that they were supposed to use up in a week. The other half got mixed nuts, tree nuts, they were almonds, walnuts, and filberts or hazelnuts. They were adding fat in the case of the nuts, vegetable protein. When you do the multivariable analysis on what correlated the best, it was the added fat. It didn't increase saturated fat, but it increased these healthy fats from these healthy foods. And as Emilia likes to point out, with the olive oil, you know, it has to be not only extra virgin, but more importantly, it needs to be high in polyphenols, which is perceptible as this black pepper staining at the back of your palate.

You need to every time you open a bottle of olive oil because it's not done that they generally polyphenol content you taste it and it should have this this this burn 10 to 20 seconds after you swallow it in the back of your palate. Those are super important at the Austin's that because they're dissolved in oil they seep into your blood vessels. They seep into your brain and your eyes and your skin, and they really correlate with good long-term health. Whereas, there's been studies that get started, Dr. Vogel and his colleagues did a study showing that all of what was bad for your endothelium, and that never made sense to me, and I realized

oh, they were using a, like, you know, ethyoxid and depleted, not one of these high polyphenol ethyoxid and all of what. So it's really important to look for those high antioxidant olive oils and then use them generously. So two comments. One is most people that think of the grocery store, myself included historically, aren't really paying close attention to what olive oil is. And boy, you only need to get fooled once, which is to say, catch what the label says to really get upset. But a lot of things that are marketed as you know pure extra virgin olive oil or anything But and I don't know how they get away with it truthfully It's it's really an embarrassment to how this stuff is regulated

But it's basically a bunch of canola oil that has some olive oil in it and they they've somehow managed to lie their way into saying It's pure olive oil. So you have to be careful what you buy. But because of that, that's the predetermined study though, had the intervention of extra virgin olive oil or nuts. And we have a rare thing, by the way, and this year, always pointing out, we have first level randomized data showing that adding this to the diet will reduce heart attack stroke and cardiovascular death.

And so, I mean, it's also, these are delicious foods when you get used to eating them. And, you know, if you want to follow a high fat sort of ketogenic diet, it should be high unsaturated fat. It shouldn't be cream and cheese and butter and red meat. It should be nuts and seeds, extra virgin olive oil, avocados, and oily fish, like so many of those five things.

I mean, you need to get a lot of your calories from those five things, which, by the way, is kind of the traditional peasant metatranian diet. These weren't, these weren't metatranians that are living high on the hog. These are the peasants who were growing their own vegetables and tending their own olive garden, then their own grapes and the red wine and that sort of thing. So, how convincing do you think are the data demonizing saturated fat? Given that so much of it is in the context of refined carbohydrates and other things, I mean, again, when you look at the epidemiologic data, unfortunately, we just don't have big

enough cohorts of people who consume saturated fat, absent carbohydrates or fine carbohydrates, it saturated fat in epidemiology becomes a proxy for people who are probably eating a lot of other bad things. So mechanistically, maybe, or otherwise, how do you feel about it? I'm actually like what people ask me about, you know, what's the most important thing of the diet? I don't mention getting rid of meat or getting red saturated fat. I mean, a moderate amount of that is, you know, again, our evolutionary history, you know,

we ate a lot of red meat and we ate saturated fat. The evil white crystal in the American diet is not salt. The worst is sugar. And sugar and refined carbohydrates are by far the absolute worst dietary villain. Saturated fat, you know, a little bit of butter is not kind of kill you, you know, like if you're a vegan, there's nothing you can eat that'll be healthier for you than like a juicy steak that's not that's not overdone, you

know, because because you're probably low in in the things like B12 and zinc and iron and high quality protein. So, yeah, it's a natural food and in moderation. I mean, I think saturated fat, excessive saturated fats, not a good idea, but we don't focus excessively on it. My wife, Joan, is a really smart dietitian. And like you, you know, we went to school till we were 32 or 33 to promote health and wellness and we got zero nothing. I mean, hardly an hour of training and nutrition.

It's just so embarrassing that it's still like that. But so, you know, she kind of taught me a lot of the fundamentals and still continues to teach me a lot of fundamentals of nutrition because this is an important thing and any good dietitian will tell you that red meat and saturated fat are essential nutrients that they're not toxic in and of themselves. So you touched briefly on salt that I know you've written about not just salt but also magnesium and that's something that's also really near and dear to my heart. Our patients consume a lot of magnesium both in the form of oxide, which we basically

titrate as high as they can tolerate from a bowel function perspective. And then we use slow mag, typically just to make sure that nobody's getting any sort of cramping or anything like that. But my thesis is there's a global shortage of magnesium in the human. Somehow we're just not getting enough magnesium. Now, I don't know why that's the case, but my proof for that, if that's too strong a word, is that when you give people back on the order of two grams of magnesium a day, they always feel better. Why is that?

Well, it's the same story with potassium, Peter, by the way, our evolutionary ancestors living out there in the wild, eating wild game, nuts, all the vegetables and fruits were getting like and fibers the same way. You know, like five times more, they were getting a lot more magnesium, a lot more potassium, a lot more fiber than we're getting today. So when you add those things back to the diet, and the best way to do it is with lots of, I mean, nuts are high in magnesium. But I agree, the other thing, so basically I think it's like getting us back

into sort of like an ideal range of consumption of a really important minute. I mean, it's an important co-factor for a lot of the most essential, sort of chemical reactions going on in our body in magnesium, this. So it's really important, but it's also makes me think that, you know, a concept that I've come to recently that I think you'll like, and you probably think this way as well, but again, if you look at our ancestors, when they would get a bird or a mammal or a fish or a squirrel or whatever, and they would

cook it or a buffalo for them, how to, and they would cook it. They would eat nose to tail, right? They'd eat the whole thing. These days when we eat meat, we usually muscle meat, which is a very narrow sort of range of animal-based nutrients. One of the things when you eat nose tail say when you're cooking the bones for example you cook them long enough to eat them you get a bunch and the skin for that matter to a bunch of collagen and you get calcium hydroxy appetite

which is a form of calcium that were meant to eat we weren't meant to eat rocks which is the standard calcium supplement it's calcium carbonate calcium glucanate those are rocks rocks. We didn't eat rocks. We ate bones. And for the last 5,000 years, we ate dairy. But a lot of people have trouble tolerating the lactose. And so we think that, and the Mediterranean diet really focuses on fermented dairy.

But getting back to, like, I think the other supplements that are really important is like an organic bone meal. That's high in, that you have to add magnesium to it because that's calcium hydroxyapatite. And if you get that up to, you know, the gram a day of calcium from there and then you're magnesium, I would agree, two grams per day. And then the collagen, because you're not going to eat enough skin to get the collagen that we're meant to get the collagen supplement, like whether it's pills or powder, is really, really good for hair skin and nails, not to mention bones,

and it's also good for putting on healthy muscle and maintaining healthy muscle. I mean, this is like ideal protein, glycine and other amino acids, that by the way, we're really meant to have an on diet. So I think those are really important supplements to that sort of healthy mediterranean, pesco mediterranean diet with the fasting.

I think that it's good to add, because it's hard to get those kinds of minerals at those levels. Do you restrict sodium in any subset of your patients, including maybe even those that are both hypertensive with compromised kidney function? We see a lot of really sick people with, you know, with class four heart failure and bad kidney disease and whatnot. And then there you have to do, be somewhat careful. But I virtually never tell people to do that less

than 1500 milligrams of sodium. And you're better off having sodium kind of in the, in the medium range, you know, from two to three grams per day. And actually a good rule of thumb for, you know, like the listeners here, and you generally healthy people, is like eat mostly whole natural foods,

which are very depleted, sodium poor, right? And then salt to taste. Because a lot of the healthiest foods you'll eat, like vegetables, nuts, fish, you'll eat a lot more of if you can salt it to taste, and make it taste good. And we add salt to those natural, or or lightly salted nuts. I mean you don't need to worry about that. That's good for you. Have some some salt in your diet when you're eating

otherwise naturally healthy wolf foods diet. All right. Let's go back and talk about that drug that I'm so enamored with or class of drug. There are at least two out there. Tell folks what an SGLT2 inhibitor is besides a mouthful. Yeah, an SGLT2 inhibitor is a diabetic drug that blocks this sodium glucose-coachransport or in the tubule and the nephron. When we filter our blood through the nephron, to the kidneys, we pull out a lot of things, your water, sodium, toxins, your rea, including glucose. And then because the body is saying, we don't trust the reason to waste those glucose, you know, we need these calories. So it reabsorbs the filtered glucose

before the urine goes out. So we figured the engineer to drug to block the reabsorption of that glucose that's filtered. And when these class of drugs first came out seven or eight years ago, I have to tell you Peter Ethe, this is a dumb idea. I mean, everybody knows the glycosuria is terrible for the kidneys, and this is like, it may be lower sugar, but in the long run, it's gonna be, but that's the beauty of science. That's why you do these big random ospocybocontrol trials. And when the first one came out, the empireg study about five years ago, like my phone

and text and emails just lit up with people from around the country, around the world, friends who were saying, did you see this? This can't be true. Keeping in mind, we've been trying to prove for 40, 50 years, 100 years since the first diabetes drug insulin came out, the controlling sugar prevented cardiovascular death. And we could improve it shockingly. Until this trial came out and it reduced cardiovascular death 38% reduced heart failure, renal failure. I mean, it was just an amazing thing.

And subsequently there's been, oh, a good seven megatriles now, you know, between three and 17,000 patients in each study randomized to SGLT2 inhibitor or placebo that shows that in fact these are the most potent drugs for, I mean, not for lower insurer, they do that modestly, but for improving cardiovascular prognosis, reducing heart failure and renal failure. And it's just fascinating to speculate about the mechanisms of action, but they have something to do with ketones, but the most shocking thing about this, that's really blowing the lid off is,

is that these drugs reduce things like heart failure, deaths, heart failure occurrence, and renal failure in people without diabetes, as well as with diabetes. So that really makes us wonder. Well, that's why I take one. And they're currently being studied, frankly, as just straight up longevity agents, for exactly that reason. And I'm actually, my interest in this even goes a bit beyond that of metformin, which has historically garnered much of the longevity

attention in the diabetes medication repurposed camp, because I like the mechanism of action more. I like what it doesn't do. Again, I think metformin is an amazing drug. I think it's efficacy and people with diabetes is remarkable. I do have my concerns about its efficacy in very healthy people who exercise at the upper limit of what we've discussed. And I think it might, it might impair there. I think it's too soon to say. I've had lots of interesting discussions with people and we're actually in the process of designing a study now to test that. But to me, this is a drug that doesn't really show any evidence of impairing the benefits of exercise and yet offers through totally different mechanisms, some of those cardio-protective benefits.

So, the good news, as you pointed out about science, is it just over time it keeps accumulating information and will get better and better answers. Turning away, you know, but so it's so fascinating to think about how this works. And I don't prescribe my form for people without diabetes. Upsetters stomach, it kind of makes you feel a little queasy. I use it on all my type 2 diabetics, but I always understand that the SGLT2 inhibitor is more important. It burns off belly fat. When you, even a non-diabetic person takes an SGLT2 inhibitor, you urinate out about

100 grams of sugar a day. So we were talking about the evil crystal compound, white, the sugar. This basically is like pulling the plug and draining a substantial amount of sugar from your body every day. It's like following a ketogenic diet without having to follow that. It raises ketones in the immune system because of the fact. It does tap into belly fat, it taps into belly fat to get the fatty acids that then turns into the liver turns into ketones. We still don't fully understand how it works, but it's an important drug class that is going to only get bigger with respect to its impact on health and longevity. Why do you think it hasn't shown an increase in UTIs or bladder cancers or things like that?

I mean, because, so seven years ago, that was my thinking, right, which was, oh, interesting idea, but you're going to have a UTI every week. No thanks. I don't see how that's a good trade-off, and it just hasn't panned out. Why do you think that is? It's sort of interesting because, well, when you think about it, the UTIs, you are getting rid of some glucose in the urine. It actually, the only predictable side effect that you see, and it goes up, especially in females, is topical yeast infections, you know,

fungal infections down in the growing regions on the genitalia. And you know, when you think about it, you are putting sugar in the water in warm, moist places. So I tell people on an SGLT2 and everything, you know, pay special attention to use a wet wipe after your nation, especially females, because there's, you know, just more surface area there to get a yeast infection on. But it is sort of interesting that it doesn't really increase things like UTI or Pylon Afritis or Euro-Sepsis. So it may be just that it's making the system otherwise healthier. You know, your immune system, your kidney function, your cut of acid system, maybe it's

just, you know, you're better able to deal with that. I don't know. This really brings it back to this point, which is, you said something earlier that I think is worth coming back to. When you take a patient with type 2 diabetes, you take two patients with type 2 diabetes, and you give one of them a lot of insulin, and you give the other one not as much insulin. One of them is going to have lower blood sugar than the other. In the one with lower blood sugar, we see less microvascular disease. We see that they have fewer amputations, less kidney disease, lower rates of impotence. Basically, any tiny, tiny blood vessel in their body does better when their glucose goes down.

But if it came down on the heels of insulin going up, we don't see a reduction in cardiovascular disease. So why is it, in your opinion, that lowering glucose with more insulin does not reduce cardiovascular mortality, which is so clearly tied to type two diabetes and post-prondial glucose? This is the key issue. Okay, and you know the answer to this is that insulin is the problem. Insolence of really super important hormone that Jason Fung and you guys and you had a really wonderful

discussion about this but insulin sort of ushers nutrients that and glucose into cells to be burned or if you're not burning you know know, in the burning mode right down, you're not exercising, you're sitting around, you're sleeping, it stores in its belly fat. So insulin is super important. If you have type 1 diabetes, in type 2 diabetes, I consider it the court of last resort. I mean, this is an obesity hormone. Insulin and cortisol are the two obesity hormones. You want to get somebody fat, put them on insulin, put them on bread and so they will get belly fat like crazy.

And I was felt so worried for these diabetics, you know, the endos would be put them on. All this insulin that I'd be telling you got to get your weight down. That's impossible. You cannot get your weight down when you're getting a lot of exogenous insulin. You're hungry all the time. It causes weight gain. It causes fluid retention. If anything, it accelerates after-else,osclerosis, you know, high insulin levels. The key is

Love you want to you want to drive your insulin levels as low as like your pulse. You want a nice low insulin They go up when you eat and then go right back down and the way you do that is you exercise you minimize belly fat You eat a diet like we were just talking about you get no sugar None of that really easily digest or refine carbohydrates. You eat a lot of fiber, a lot of low glycemic fruit, but more, more, more sort of non-stargy vegetables. You eat modest amounts of lean protein. And a little bit of saturated fat, don't hurt you. You eat a lot, like 50% of your calories from unsaturated fats, from those, you know those nuts and all the while in other colors, guacamole and salmon and sardines and childhood.

And you will have, you know this, from where at a glucose monodrivor and a glucose monitor for a while too, being non-diabetic, I found it a really great behavior and modification thing, but when you eat that way, you don't see your glucose go up at all. So when your glucose goes up, your insulin doesn't go up.

And when your insulin stays low, your vessels are happy, you're not put non-belly fat. We wrote an article called, you know, insulin is a cardio toxic medication. I mean, we want to minimize the amount of insulin. Unfortunately, there's new drug plus SGLT2 inhibers, GLP1 agonist, that's semi-glutide, and dulyglutide, that's a couple others.

These two together, along with the metformin for diabetics, amazing rocks. They all lower insulin, they all reduce fat, belly fat, and they all improve cardiovascular prognosis. And by the way, you know, a lot of it has to do with the effect on insulin. Tell folks how the GLP1 agonist work. And we might as well round out that trifecta. Yeah, so GLP1 agonist work. We might as well round out that trifecta.

Yeah. So, GLP1 agonist work by supplying a hormone that tends to wane in people as they develop type 2 diabetes. This is a hormone that tells after you eat, it tells the pancreas to give a shot of insulin. And when you're not eating, it also tells it shuts down glucose, production and deliver. So, you're making less glucose. Gluconeogenesis, when you don not eating, it also tells it shuts down glucogone production in the liver. So you're making less glucose. Gluconeogenesis, one you don't need to be. And that's one of the problems when you're eating this junkie diet,

you get these intratenolabels, you get low, you get this gluconeogenesis. So you wake up in the morning, even after not eating for eight or 10 hours, and your glucose is high, because you're making glucose when you don't need to be. So this basically restores a hormone that is low and it sort of balances out kind of lowers fasting insulin and raises post-pranial insulin

and infotions also slow bowel motility so that it slows absorption so you don't get the big spikes in glucose and actually, you know, kind of makes you feel full faster. So these are wonderful drugs for weight loss. I'm using in some of my patients now, high dose, summer glucose type, and it'll lose up to 10% body weight in a very safe way. I mean, even in non-diabetic, it's a very safe way to get your weight down.

And I'll combine it with SGLT2 inhibitors and non-diabetic works, reduces cardiovascular risk, people on GMP want agonist, tend to complain of some, when you first start it and when you does, titrate it every week, some constipation and or nausea, but those go away with time. And it is FDA approved for weight loss, isn't it? At least one of them is, right? It is. You want to, um, lyracletide is 6th-hand. But it's a once a day drug this you know the semaglutide will be approved in the next year as a once a week drug the way we

use it for diabetes and at a higher dose 2.4 million rounds rather than one milligram for the top dose and you know it's shown it's just best ever way production and you know it's sort of an alternative to to bariatric surgery for these really overweight patients. And... Wow, I didn't realize that. So you're telling me that you can now take a GLP-1 agonist once a week with a sub-Q injection

and achieve comparable levels to the normal daily injected routine, because that's historically been one of the barriers. Better cardiovascular reduction. It reduces heart attack, stroke cardiovascular death, better than the daily one, the little arachyletide. These are also revolutionary drugs,

but the cool thing, they're very safe otherwise, you know? And whereas the SGLT2 inhibitors, you kind of reduce heart failure and renal failure, and overall cardiovascular mortality, and all cause mortality in sicker people. This reduces more the atherosclerotic cardiovascular disease. It has a strong effect on MI stroke and you know those ruptured plaques we talked about at the beginning.

They cause weight reduction from due different mechanisms in the vaccine. They improve cardiovascular prognosis from due different mechanisms in the vaccine and they really work well together. It's a phenomenal combination. Well, we can't have a discussion about medications and cardiovascular disease without talking about statins, which you've written about a lot. Certainly, we'd have to be in the top three most prescribed classes of medications out there. You know, I'm kind of a five-statin guy.

There's a lot out there, but there's probably only five that I'll use in patients. Every physician, I think, who prescribes these, has their own little secret alchemy around it. When they're using live-alow versus prevastatin, versus crestor, versus lipitor, etc. But let's talk broadly about them as a class. Obviously, a type of drug that inhibits the synthesis of cholesterol, which is its direct action, but the money may come more from its indirect action, which increases the LDL receptor on the liver, and you're pulling that APOB bearing particle out of circulation, and you're having this pretty pronounced effect in terms of LDL, C, and APOB reduction, second really now only to PCSK9 inhibitors.

But rather than talk about that, although I'm happy to hear your thoughts on that, I wanna talk a little bit more about the potential other benefits of statins, because I think this is where most people do believe there are pleiotrophic benefits of statins, but they're harder to quantify. And I'm sort of curious as to what

your thinking is on when you want to bring a statin in, is it also something you use in patients whose APOB might not be that high, but for whom you're looking for this other benefit? I mean, it's a very triopic effect, if you will, on statins, is there a study just this week, came out that people who were on statins seemed to have some better sort of resistance to severe COVID infection. And it may be that the people that get a lot of inflammation

are the ones who are likely to have a bad outcome with the COVID infection. But in any event, they do have anti-inflammatory effects. And we use them a lot. And I'm always arguing with my patients about statins. And they'll say, have you read about these things on the internet? These are like, and I've pointed out to them, in the history of science, in the history of medicine and randomized trials, there's never been a cross of medication that's been so

thoroughly tested in gold standard randomized placebo controlled trials. Last thing I have to use, there's like 500,000, half a million people in various randomized trials shown that if you have heart disease, especially if you have cardiovascular bed, they will help improve your prognosis. They reduce MRI stroke, cardiovascular death, probably it will cause mortality to high-risk people. Pause for one second, James. I agree with you completely.

There is no drug, no class of drug. I spend more time defending than statins. Why is that? Why is it that the internet is absolutely crazy with this obsession that the statin is a drug planted here by foreign operatives designed specifically to kill us. It's crazy. It's a combination of things. Number one, and I was kind of skeptical about this, but then I started taking a statin back about, you know, when I was 45 and I had that calcium scar.

And when I was working out hard,, like my muscles were hurt harder. I mean, like they would ache, they would ache worse after a hard workout. And then so I started taking constant Q-10 and switched over to a more of a less potent one. And sure enough, they got better. So they frequently are associated with these new side effects, like muscle aches.

And some people swear that causes some brain fog, some sort of mild cognitive impairment. But a lot of it too is, you know, is sort of the no-see-bow effect, the voodoo effect. You know, they read about this in the, you know, and there's all sorts of people, you know, trying to capitalize on selling people alternatives to statins. That being said, I argue with people about statins who really need that. The 55-year-old just had an MI who tells me, you know, I'll do anything but take a satin. Fortunately, now we do have other good options. Zedabyte, lowers cholesterol by reducing absorption by blocking the Neem and Pick receptor,

and PCSK9 inhibitors, which just just for long-life early-ale receptors, both really elegant ways to lower cholesterol by removing it from the circulation without poisoning the cell's ability to make cholesterol. So that's really, really important, and I know you were talking about the day spring about that, and I completely agree. So we have an option for those people who are statin intolerant, because a zetamide and PCS came out in hibernates, they work synergistically like statins and PCS can not inhibit us or a Zedemaib and statins. But for people who have a zero calcium score who are relatively low risk, we do the Mase of Risk Calculator with a AACVD 10-year

risk and they're under seven, lots of times they're one or two or three. Like it's hard to improve somebody who's got such a low risk. And then I say, you know, let's not get overly shook up about your LDL. And let's just, you don't need to stand, we can stop your stand, we don't need to start it, whatever. And we'll focus on diet, the next time I have a lifestyle. But in middle-aged people, I need to see that zero calcium score or low calcium score to do that.

But yeah, stavans are a wonderful tool, they're cheap, and we use a lot of them, but we also stop a lot of them. And I think for, I'd be fascinated to hear this, I've thought about writing a paper on this topic, because there's nothing out there in literature, but you kind of touched on it on one of your sessions. I think it was with Tom Day's, Brim, that to the extent that statins do sort of impair a

cell's ability to make cholesterol, it does not only in the liver that makes mostly cholesterol, but it doesn't have an brain. And people say it doesn't matter about getting cholesterol too low because cells can even brain makes its own cholesterol. If it does, if it needs it, if it's not poisoned, the HMG is in poison by the statin. But if it is, that gets into the brain and it can't make its own cholesterol. And when you look at the mentored people, they have lipid depleted brains.

You know, this shrunken brain, I mean, there's a good study shown that omega-3 helps to keep your brain plop, a high omega-3 diet. And for that same reason, I have some sense that we might be better off using non-statin approaches to lowering cholesterol like PCS, K9 inhibitors, omega-3, azetamide, a good diet, and other people that if we want to maximize sort of cognition and reduce Alzheimer's disease down the road. Tom, of course, works very closely with us in our practice, and that's absolutely been our approach, which, of course, puts us at odds with many of

the people that are in the very strong pro-heart camp, very organ-specific camp. We look at two markers of cholesterol synthesis. Does monstral and lethosterol? We monitor them very closely. And there is a small body of literature that says, at least in high risk people, maybe people who carry one or two copies of an APOE4 gene, that very low levels of dismaster all and or lethoster all in the presence of statins may be a predictor of increased risk. And we just, in that situation, that based on all the reasons you've laid out, play

to the precautionary principle. And frankly, you know, our application of that is, there's probably only two patients in my entire practice that are going to walk around with a Dismostral below 0.5. Because there are so many other options, if we need them, that we don't need to overly suppress cholesterol synthesis. So only in the most high-risk cases of cardiovascular disease, when we have no real other options, then we do this. But otherwise, you're right. I mean, we're incredibly liberal with the use of Zedia. And I think physicians are becoming more liberal with that, which I think is great,

coupled with, frankly, preva statins, my favorite statin, if I can get the results there. You know, it's so mild, also anecdotally, seems to produce less symptoms. It also raises, it doesn't raise glucose the way a tore of a statin or preva statin will. And it doesn't increase risk of type 2 diabetes. And when you use it with a zetamide, which again, we have a great study, the utopia study in primary prevention.

Zedema reduced cardiovascular events by 30 percent, and we also have the improved study that showed that if you combine it with a stat and it reduced cardiovascular events, so we have really good first-level evidence about a Zedema. The only thing I would disagree with you on, and disagreeing my P2 strong on word, is tell you how I think about things a little bit differently is. I don't look at a 10 year risk calculator. That's one area where in my practice we just have to do things a bit different, which means we have to deviate from guidelines because I agree with you. Look, if if a person 10 year risk is 2% and their calcium score is zero, but their APO B is at the 80th percentile.

The textbook answer is do nothing. Once you've exhausted all the lifestyle modifications, my view on that is if you're 40 years old and your 10 year risk is zero, congratulations, but I'm playing a different game, right? I'm really in this camp of Alan Snyderman that says, we have to be taking a 30 and 40-year view of cardiovascular mortality. And that means I can't look at a 10-year risk calculator. I have to take a longer arc. And sometimes that means primary prevention

is adding drug to treatment of all other variables, even if the calcium score is zero. But again, that's a patient's decision based on their appetite for risk and their appetite for longevity. So I completely agree. And you know, we don't, at least I don't know of 30-year risk calculators, so that calculator you're using is in your head. And you know, that's a very good calculator.

But one point I would make is that in those kind of people, and I would say myself included, I don't take a stat and I haven't for years. I don't have a lot of risk factors, but it did have a little bit of calcium on it, I checked it years ago. So I'm sure I have more now. Stadden is one of the accelerated coronary calcification, by the way. So I use Zetamob with a PCS K90 never in myself, because it doesn't have any side effects. New here, those have side effects. I mean rarely rarely and they work through very elegant mechanisms that don't distort your sort of milieu of cholesterol homeostasis whether it be in the brain or or or wherever. I mean this is just

sort of making you as if you were genetically one of those gifted people the tends to run a nice low cholesterol. Well, that's interesting. You know, that's sort of where I've migrated almost. I'm a low-dose prevastatin plus PCSK9 inhibitor, and I was thinking about doing the experiment of switching to from prevastatin over to Zedia to C. And the reason for me is I had a calcium score of 6 when I was 36, and that's in the presence of, you know, all the exercise and stuff. Now I would argue at the time my nutrition was horrible because it was a quote unquote traditional athlete's diet of a gallon of gatorade a day or powerade.

That's the old athletes added, you know, if you run the engine hot enough, you can burn any fuel. Yeah. But Peter, I would say, you said, you know, you know, with Kelsen score of six when you were 36, despite your exercise, I would say maybe because, you know, when you're swimming 20 miles over the height, you know, like you were hammering, hammering, and really intense exercise will accelerate

cornering calcification. Yes, I have actually thought about that, and I repeated the calciumium score in 2017, so that would have made me 44 or whatever. It was zero. Wow. Now it's very interesting because, as you know, as the scores were...

That was for Verra by the way. Yeah, well, and I talked about this at length with Bob Peters, who is, I think Bob Peters and Steve Wolf are hands down the best cardiac radiologist in New York City. Peter's and Steve Wolf are hands down the best cardiac radiologist in New York City. So I had a CAC and CTA done with them, incredibly low radiation, by the way, 2.2 millicieverts for a CTA and CAC. And the question was, hey, is it an artifact? When you have a calcium score, go from 6 to 0, we're just sort of missing

it because there was still a little blip in the end of the end of the LAD in that 2017 study. It just didn't register as a full calcium. So, I'll probably go back in a year and just repeat the CAC because I am curious. The point is, like, even if there's a little calcium there, it's really, really unusual for the calcium score to go anywhere up. And usually it goes up like 25, 30% a year or more with calcification. So it's kind of like we wish our investments, you know, like the compound interest, you

know, it really can accumulate. And I'll have to say, I've probably read 150,000 calcium scores in the last 20 years. Because we've probably done 600,000 in our practice, and we do 50 or 60 of our day. So, you virtually never see that. And now, at a low level, you kind of nipped it in the bud with your better diet, and probably tapered your exercise, I don't know. But in any event, I saw a distinctly unusual pattern of regression in a calcium score in a good friend of mine who's an executive. We'd been on a

statin for decades at a calcium score of like 1200 if we had everything going up. No diabetes, but you know, it's obese and we switched them over because I have some eggs to a PCS cannot inhibit end of zebimide and a calcium score a couple of three years later had gone down from like 1200 I mean from now it is like 1400 it was like two or 300 lower you know more than the margin of error of the test that made me think you know one of the one stat is do tend to increase corner of calcification, but I bet PCSK9 inhibitors don't. And certainly that anecdotal experience. And I bet Zetemov doesn't either. So I saw an abstract, but I don't know if it ever made it the publication that actually suggested PCSK9

inhibitors decreased calcification. That was my anecdotal experience. Yeah, now of course, I don't know what that means. Because in the end, I don't typically re-scan patients. If I have a 50-year-old who shows up with a calcium score of 100, I have all the answer I need to know, which is we need to be way more aggressive. And there's nothing I'm going to glean by re-scanning you next year to find out your 120 versus 80.

It will not change our management. And it just discourages, you know, somebody who's doing their best. Yeah. Very discouraging to think. And then you have to explain, well, you're on a medication that does accelerate it, but it reduces your risk despite that because it's making the plexus less prone to rupture. And I'm the same way. I rarely, the only time I increase in these people who aren't doing the same right thing, they're not taking their medications or they're still smoking, or they're not exercising, then I'll check and say, you know, it's gone up

from a thousand, a thirteen hundred or a hundred to two hundred, you know, you need to get on this, but the dirty little secret is that it goes up in most people. But nonetheless, we can prevent cardiovascular events with all these strategies we're talking about, despite the Ciorna Cielcin. I'm so happy to hear about what you're doing a $50 CAC really at that point when you can get that level of a diagnostic test for less than the cost of a nice dinner, there's really no barrier to entry. And then those people that have a positive score, we get them over in our cardiometabolic clinic, cardioreal dysclinic, we have two different clinics, one focusing on the glucose side of things and the SGLT2 and Iversal, wellness clinic, we have two different clinics. One, focusing on the glucose side of things,

and the SGLT2 inhibitors will geopieoonagonists and metformin and weight loss, and the other one, augments, the standard risk factors of lipids and whatnot. But we get unplugged in, and we see them two, three times a year. We make sure there's nothing like feedback, right? And we're a big fan of getting lipids tested, and test these various markers, HSCRP, A1C, a lot of things.

We follow because when you know better you do better and people need feedback. To round out our discussion on the pharmacologic tools, where are you on the high doses of EPA versus EPA DHA combined? Obviously these are becoming very popular tools in the toolkit. Again, just at the pharmacolevel, also at the supplement level, if you pick your supplements right, how do you think about these in terms of heart health and brain health? So, again, super enlightened question, and this is like one at the crook, so some of the most exciting stuff going on right now. So, we'll make a three, like we're talking about some other nutrients,

we're eating like maybe an order of magnitude less of that, that what we did in our evolutionary experience. Some people argue, you know, when we get access to shellfish and seafood is when our brain expanded, you know, three or four hundred thousand years ago. So omega three, you know, like 20% of the dry weight of the brain is polyunsaturated fats, and it's favorite polyunsaturated fat to plug into those membranes, and the neurons is a DHA. EPA is also, you know, another super important omega-3, and a lot of my patients come in and they stop their official, they stop their omega-3 because their doctor told them, oh,

no, these don't work. And as you pointed out, many times in your writings and whatnot, even randomized control trials can be wrong, can be large and wrong. If you're testing the wrong people, if you're using the wrong dose. And a lot of those trials were done with small doses. And these big metanalyses, not to mention the reduced-it study, which recently tested the four grams of EPA and people with had heart disease or diabetes or other risk factors, you test and how to triglycerides above on 50. So you test the right people,

give them a nice robust dose and you see these spectacular results from a nutrient. And a lot of the reasons doctors dismiss it is because again, we don't get taught anything about nutrition. We have an inherent distress that anything doing diet or supplements is worthless and that is so untrue and omega-3 is exhibit A. So the latest meta-analysis, there was one just out in male clinic proceedings coming out this coming week. I wasn't on this but one of my best friends was Chippell V from down in in Oshner. This is done with some Italian collaborators but it's a really good meta-analysis of all the randomized data with omega-3, and they show for every gram per day of EPA-DHA taken, you reduce risk of M-I cardiovascular death, and even trends towards all cause of mortality.

But the point is, like a lot of the studies just used to 1 gram, but if you use 2, 3, 4 grams, you see these really remarkable, like in the Reducit study, 25 to 30% reduction in cardiovascular events and all cause mortality, even in people, especially if they have triglycerides above 150. The question about whether it's EPA versus DHA, you know, the evidence in that trial was EPA, but if you look at the meta-analysis, you know, as long as you're getting that dose of EPA and DHA, I mean, I think it's important to have some DHA in the supplement too, just because, again, it's important for the membranes

and our evolutionary experience would suggest we weren't just eating EPA, we're using the combination. I agree with you completely on that, and this is, I put this in the category of things I can't wait to learn I mean sometimes I just get excited about the state of natural knowledge and how it continues to evolve and I Can't wait to see five years from now what we know on this question because I was a bit surprised by the combined EPA DHA trial I really expected that to be a favorable response especially in light of what we saw in the 4g EPA, Vesepa trial.

So again, we just have to see where this thing goes, but I agree with you. That was the strength trial you were talking about. That's right, there was halted early. So it might be that 4g of EPA in that concentrated form is the way to go in a super high-risk person for cardiovascular disease, but a combination of EPA and DHA through food, oily fish, as you said, might be what's conferring the real benefit. That's how we got it in nature. I think the broader question always comes to, is there a harm of higher doses of EPA and DHA? And I feel very confident now that the answer to that question is no.

Provided you're getting your product through a clean source, and the answer is no. And so we have zero affiliation with any companies that produce any of these products, and we had a third party do a validation of Carlson's, which is the one that we have preferred for our patients, and we found it to be pure without contaminant and it contained what it said it contained. So I'm always happy to pay that little bit of a premium for that product to at least get it over the counterversion that's good. So I don't have to sort of fork over for a prescription version. Yeah, I'm the chief medical officer for a company called Codiotab. So we, you know, I don't get paid anything from them, but that's kind of my goal with them too. And we also source it from Norway.

They know more about purifying, concentrating, detoxifying, omega-3, than anybody in the world, as far as I'm concerned. And usually go over to Scandinavia there and visit with leaders and not just to see what their latest and greatest stuff is. But yeah, this is a food. And I think it's super important, not only for cardiovascular health, but Peter, the latest data on mental health is really important. Again, this is a fundamental component of cell membranes that most Americans upwards of like 90%

of Americans aren't getting enough omega-3 in their diet. And it correlates with depression, ADHD, suicide, cognition, dementia, all those things. I mean, this is like a super easy way to marketly improve mental health by wife's parents, constantly harping on this, that, you know, there's all this violence and suicide and depression. And like the basic thing to do is take a nice high dose of omega-3 every day. It's harmless, it's cheap, and it has profound benefits. And lots of times you can keep people off of antidepressant medications at, and a well-absorbed procurement with high dose omega-3 is as good as anti or better than any

added present out there. And they also have to improve brain function. And again, your doctor won't prescribe these, but these are very, very effective ways to improve mood, cognition, and probably reduce dementia in the long run. We have a paper coming out of center of coptia, of the journal Alzheimer's disease, showing that a highly absorbable perkymen, a therapeutic cure in a randomized trial. The study was a TNF alpha inhibition for preventing dementia and TNF alpha, as you know is this master hormone of inflammation, and there's some really fascinating, which we outlined in this systematic review, that the biologics that reduce TNF

alpha, like a 10% is the best one. It's this decar receptor for TNF alpha. And so it reduces inflammation. And there's multiple big studies of millions of people in databases. This is all observational data, but that it reduces risk of Alzheimer's disease 60 to 70%.

Now those are expansive biologics that sometimes can cause serious side effects, but Kirkman is the active of the use of turmeric. And if you use a highly absorbed one, you get some pretty impressive reductions in TNF alpha that have been correlated in small randomized trials with reduction. And there's good animal models on this too.

I mean, it's one of the most exciting things to me right now is I really think this is easily the most exciting thing ever for maintaining cognition for preventing Alzheimer's disease and it still needs to be flushed out, but there's some very good biological plausibility behind it and some fascinating animal data, human data, and even some small randomized trials. You know, working with Richard Isaacson who I've interviewed for this podcast and I'll be interviewing again shortly We've sort of put together our in-house kind of playlist for Basically once we identify patients that we deem high risk for Alzheimer's disease Which we we define as age over 60 a relative that as a history of Alzheimer's disease or at least one copy of an apoe for gene

Or some other gene such as an anti-TNF gene or Tom Fordy, or one of these other genes that tends to be associated with Alzheimer's disease, plus or minus APOE4. We just have sort of a full-court press approach, and one of the things on that list is indeed Thericumin. For exactly the reasons you've stated, I became pretty impressed with those data about two years ago, and so I was excited when you sent over that manuscript last week. So you noticed that Richard Isaacson was a co-author on that paper. Asma's Gary Small from UCLA, who's in my opinion, those guys are two top brain scientists in the country for things like preserving cognition.

So yeah, I think that the people who are best informed on that would agree with you on that on that approach. You know, I guess closing thought, James, is I'm just impressed by the breadth of your curiosity and obsession. You know, again, interventional cardiology is a niche sport, right? It's a, you know, you're a cath jockey at that point. And you sort of left that behind, and the world has become your oyster, so to speak, and you're now interested in the role that Theric human can play in inhibiting tumor necrosis factor in the development of dementia. I mean, do you ever kind of look back

and reflect on the journey of your career? I'll pause there before asking another question. I just followed my heart and what I was most interested in and I like to joke that I mean, I'd be doing the same thing right now if I wasn't getting paid. I mean, I love what I do. And I think of life as, you know, like this gift of we have our time here on Earth and it's about like helping others and making a positive difference and I'm just so grateful that we live now where we have all these tools and like you say it's just so exciting there's all this emerging data for people who are trying to pay attention.

You kind of like that line from Dickens was it was the best of times it was the worst of times. You know there's a lot of people out there that suffer from all sorts of terrible things. A lot of it's lifestyle related, and it's not their fault. I mean, it's like this whole world is set up to minimize activity and maximize calorie consumption. But there's also people who are paying close attention, and we have all these powerful tools and use this information

to help each other and to live not only longer but more sort of active and fulfilling and enjoyable lives. So to me, it's just a blast. My last question then, James would be, if there's somebody listening to this who wants to go into medicine and feels or is in medicine for that matter and kind of feels the same conviction you do, which is the real answer is in preventing disease. And whether that's their passion is in cancer or cardiovascular disease or neurodegenerative disease, diabetes, whatever the case might be. You know, you said it at the outset, nobody's reimbursing really for prevention. You've got to kind of create your own path.

What would your advice be to somebody who wants to become a preventative oncologist, a preventative cardiologist, a preventative neurologist? How would you advise them to craft their way? Well, that's a difficult question, but I can just tell you that it doesn't have to be all or nothing, even like the cath jobies, like they say. Some of my partners are, your cath jobgies, like they say, some of my partners are, your cath joggers, you're very enlightened about lipids. And you don't necessarily have to do it all the time, but you need to be able to be well versed enough to strongly endorse

it. And I mean, I'm in a big group of 65 cardiologists with another 50 nurse practitioner or physician's assistants. And so I can kind of carve out that niche and live there most of the time, although I still rather than the hospital and not sort of thinking, but in the future, this is going to be an increasingly important part of medicine. People are going to understand, you know, they'll pay a lot to have their life optimized,

not only for longevity, but also for enjoying life and being fully functional. And I think it's never been a better time to get interested in prevention. It's a lot of blue sky out there and a lot of promising therapies and lifestyles and strategies that we can deploy now. I've enjoyed this discussion immensely. As is the case with virtually every podcast, I learn at least one thing, and in this one, I've learned many things that I can't wait to take back to my patients and frankly to myself.

So thank you for your generosity, and thank you for continuing to mentor me. I've considered you both a friend and teacher for many years now, and I look forward to that continuing. Thanks for the opportunity, Peter, it's really my honor to be on your show. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription.

Now, to that end, membership benefits include a bunch of things. One, totally kick-ass comprehensive podcast show notes, the detail every topic paper person thing we discuss on each episode. The word on the street is, nobody's show notes rival these. Monthly AMA episodes are asking me anything episodes, hearing these episodes completely. Access to our private podcast feed that allows you to hear everything without having to listen to spills like this. The Qualies, which are a super short podcast that we release every Tuesday through Friday,

highlighting the best questions topics and tactics discussed on previous episodes of the drive. This is a great way to catch up on previous episodes without having to go back and necessarily listen to everyone. Steep discounts on products that I believe in but for which I'm not getting paid to endorse. And a whole bunch of other benefits that we continue to trickle in as time goes on. If you want to learn more and access these member-only benefits, you can head over to peteratia-md.com forward slash subscribe. You can find me on Twitter, Instagram, and Facebook, all with the ID, Peter, Attia, MD. You can also leave us a review on Apple Podcasts or whatever podcast player you listen on.

This podcast is for general informational purposes only. It does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take conflicts of interest very seriously for all of my disclosures in the companies I invest in, or advise please visit peteratia-md.com forward slash about where I keep an up-to-date and active list of such companies. Thank you.