#134 - James O'Keefe, M.D.: Preventing cardiovascular disease and the risk of too much exercise.

Hey everyone. Welcome to the Drive Podcast. I'm your host Peter Attia. 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 peterattiamd.com subscribe Now without further delay. Here's today's episode. My guest this week is Dr. James O'. Keefe. James is a cardiologist and medical Director of the Charles and Barbara Duboc 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, dyslipidemia essentials and Diabetes Essentials. James has also co authored with his wife Joan the best selling consumer health book, the Forever Young Diet and Lifestyle. He is 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 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 de force discussion of many of the pharmacologic agents that some of you have probably heard of. And frankly, even this discussion taught me quite a bit and actually invigorated my knowledge for this space. So I always enjoy talking with James and isis. 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, albeit 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'd 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 as my sort of constant educators. So this is going to 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. The other thing I'm really impressed at because a lot of my fellows in Residents and kids will talk to me about what they heard on Peter Attia. So your audience is particularly, if I might say, tuned in intelligentsia, interested in health and well being, and I think you have really curated a remarkable audience.

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 p. 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 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 at or above threshold. And you presented data basically suggesting that that was harmful potentially and that 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 want to 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 heart, whether it's putting stents in the coronary arteries or putting in pacemakers. These days it's expanded to you fixing the valves. It's just the technology is just absolutely spectacular. These days we can put in valves. It's become our default way of replacing a valve now is through the artery. So it's a really cool field. At the time, I trained at the Mayo Clinic for internal medicine and cardiology and then went down to Kansas City at the Mid America heart Institute in 1988 to work with Jeffrey Hartzler, who was the world's expert in interventional cardiologists. He invented infarct angioplasty. That is somebody who's having a heart attack. He had the sort of chutzpah 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 nationally at the meetings. But it turned out, you know, to be a game changing therapy. And now it's the standard across the world for, you know, for treating angioplasty. So I went there and worked with him and started off my career and maybe I'll back up saying, you know, I'm like you, I love exercise. It's how I calm Myself down, cheer myself up, whatever. I mean, it's just always my kids say it's how I've been self medicating my 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. She 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. And I was just fascinated by the 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, through my cardiology training and then do an interventional cardiology. And I did it for about a year or two and then I realized this back in the night. Then we're only doing balloon angioplasty. So we balloon these, dial, you know, dilate these, these vessels up in elective people who are having angina. And, and then they'd be back in six months or a year with more blockages. And it just don't, I mean, this is not the ideal way to treat coronary 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, when, 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 just continued to blossom. So that coronary disease these days, even though 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 electively. You know, we have, we have the tools. And so it's also just the more enlightened approach. I mean, it doesn't pay well. You know, 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 proactively 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 explained, 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 lad in the circ, right at that widowmaker location, which is named appropriately. How many millimeters is that in a normal healthy 40 or 50 year old?

So that's typically about 4 millimeters. 4 or 5 millimeters. The left main coronary, you know, so not quite half a centimeter, which is a third of an inch.

Yeah, so we're talking tiny, tiny little things. Yeah, it's 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 cardiologists 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's 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 stents in people. There's certainly a lot of economic benefit to certain parties, but there's not an enormous clinical benefit outside of acute mi, and we can bifurcate into which types of mi, et cetera. But 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. We think of this, and it's very logical, which is why it's been one of 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 flood paradigm for 40 years now. And you're right, as logical as that is, it doesn't really turn out to be true if that 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 pustules filled with oxidized triglycerides and LDL cholesterol, then attract the monocytes and the macrophages that elute these inflammatory markers, and they thin out the collagen overlying the zit, and it ruptures and it drains and heals. If it's a particularly bad zit, you end up with a. 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 pustules filled with nasty, yellowish, inflamed, and they get hot, they rupture, and instead of just draining, they attract thrombi because they think there's a rent a hole in the vessel. So a thrombus forms platelets and fibrinogen, and over time, it heals, if you're lucky enough, and most of the time you are. This happens time and time again, getting through decades before it gets to the point where one ruptures and then completely closes it off. But in the meanwhile, every time you get one of those inflamed zits that ruptures, you get the growth factors stimulate the growth of the smooth muscle and the collagen. And if it's a really bad zit, you know, eventually you'll calcify. And those are fossil evidence of previous badly inflamed zits, if you will. So this is like really everyday common Stuff, but we know how to prevent it. But going in with a balloon and addressing one little area 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 diet and lifestyle and exercise, keeping the lipids down and 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 through the endothelium and become macrophage 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, you know, 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 thrombo cells 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 100 and change, placing him between about the 75th and 90th percentile for age located in three vessels. He was visibly alarmed. Right. He said, this is really bad. And, you know, the stenosis in each of these by calcification were, you know, in the ballpark of 30 to 50%. 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'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, 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 men over age 40, women over 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, 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 you 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 score on them and it's zero. And you say, well, you've gotten through 53 years of life without making any hard plaque. So we're not gonna, like, we maybe don't need to use a statin on you. Maybe we don't. Maybe we can tolerate it. Seems like you're doing fine. On the other hand, there's a lot of people who have relatively minor risk factors that are 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 for a calcium score. I mean, I often show the residents, like we put the Hounsfield area of interest over the left main or the LAD, and it'll be 800 to 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 speck 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 described, they come in and say, why do I have this? I'm doing everything right. I said, well, you probably have a bad family history, right? Yeah, yeah, I do say, well, you know, 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 modifiable 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, 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 of exercise. And by the way, at this point, Peter Attia 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 got to get the dose right. Say you're using Carvedilol, one of my favorite drugs, and you give somebody who has afib or recent infarct or high blood pressure, you give them carvedilol, but it's 1 milligram, you don't get any benefit. Right. On the other hand, you give, you give them 120 milligrams twice, twice a day. So if you give them 100 milligrams twice a day of carved alone, it's a disaster. I mean their blood pressure is going to be low, they'll feel terrible. I mean, right, they'd have a hard.

Time getting up off the couch.

Exactly. Right. So. Well, 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 brisk walk, 15 minutes a day, they would get like a 30% reduction in serious cardiovascular disease. 15 minutes a day. Now ideally we, you know, we say 150 minutes a week is sort of a lower limit benefit. But the point is that early steep limb of the, of the survival reverse exercise dose falls steeply, your benefit goes down 30, 40, 50%. But then for the last uptick, the people doing the most extreme doses of 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 overdo it you could make yourself worse. And to be clear, it's only like 2.5% of Americans who are probably overdoing exercise versus at least 50% who are under doing 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, kind of will sort of discourage people from not eating as much. I mean, it's the mirror 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 Catalina channel like 15 years ago, right?

Yeah.

And I mean, that's 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 5 liters a minute of blood, when you're doing high intensity intervals or when you're swimming across the Catalan Channel at, you know, I mean, a fast rate, I mean, you did that 20 miles in like 12 and a half. I mean, 10 and a half hours.

So actually I think cycling is a, 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. So for me, the maximum area under the curve heart rate was a one hour time trial. So. 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 max, my heart rate would be about 172 for that type of a race for an hour.

Well, it would take less than an hour, probably.

Yes, exactly. It would take about 56 minutes, 55 minutes maybe.

No, but 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, you're, you're, you're using big muscles, you know, your blood pressure is also probably 200. Your systolic pressure, your pulmonary pressure is probably 80, 60, 70, 80.

I mean, let's give people some metrics of normal. So for. Obviously doctors listening to this will know what we're talking about, but let's take a step back. So let's say my blood pressure is, I have 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 blood pressure checked?

You know, this is just the pressure that is exerted to pump the 5 liters of blood around your, 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 2 or 3 or 4 millimeters of mercury up from the legs. And, and that's a more difficult physics problem. Right, because you're overcoming 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, 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 115, even a normal 115 millimeters of mercury is, 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, as it receives the bolus of blood, everything expands. And then when the aortic valve shuts, then those vessels, they rebound a little bit and they keep the. Take this sort of pulse tile bolus flow and turn it to more of a laminar, less bolus 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 Ganz catheter placed in me. So what would you assume my pulmonary pressures are?

Oh, they'd be low. Like 20, 25 over 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. Arteries. Let's just assert that my heart rate's 45 beats per minute. And you said my Cardiac output is 5 liters per minute. So that means every minute my heart sends 5 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 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 conditioned 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 a good heart should have about 3 or 4 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 and exercise program to sort of minimize the number of heartbeats per year. Okay? And it does involve exercise, but it doesn't involve, you know, it doesn't involve Herculean efforts of protracted 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 at 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, like Lance 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 Alpe d' Huez 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 2 and 3 liters 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 5 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, right, 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, how much volume it can accommodate with each beat is an important factor. And I remember Miguel Indurain 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 arterioles and venules dilate up so that the resistance goes down. And the heart is actually not just a pump, but it like it wrings out the blood, it shortens and twists. And when it's going fast and you're exercising, 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 that from 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 the point is to get back to the underlying concept is that you could imagine when you're going that hard and your blood pressure's up and your pulmonary pressures are 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 6x 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 drop out. 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 at a sort of a comfortable walking pace. Lots of times they're carrying things or they might be, they might be lifting, chopping, swimming, you know, whatever, building. And occasionally critical times in the hunt or whatever, you know, they might be sprinting, although the younger members in the tribe would be assigned that task because they're faster runners. But we're not really designed to do what you did when you were doing these, like you still do, you know, do these really long bike rides, the chambers or marathons, ultramarathons. You know, the chambers dilate up and we have enough circulating buffers in our bloodstream because this is like an engine when, you know, like an exercising muscle uses fuel, glucose, fatty acids, ketones to create energy. But it throws off exhaust. And when you're exercising that hard, it throws off a lot of exhaust in the form of free radicals. Okay, we have a lot of circulating buffers in there to basically neutralize those free radicals. But we, we deplete that after five 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 too. After you've depleted Those antioxidants, after 45 or 50 minutes, you start like searing the inside of your vessels, those endothelial sensitive endothelial linings with high, high free radical levels. And you also start over taxing the heart muscle. And I'm not saying it's not a big deal, especially when you're young. You know, 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 or 25 or 30 or 35 and maybe even 40 or 45. But after 45, it starts more likely taking a toll. You start seeing, you know, troponins will rise and nt pro Mbp will rise after really, really strong efforts like, like a marathon.

Tell folks what those Markers mean, Because anybody who's been to an ER with chest pain will know what a troponin 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 troponin 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, you know, we usually associate it with, like you say, heart attacks, where the artery closes off and the muscle is starved for oxygen and it dies downstream in that, unless there's good collaterals. So that really raises our eyebrows and gets us into action when we see an elevated troponin. But a lot of people, I mean, upwards of half or more people after a marathon will have an elevated troponin. It's just the vest at that high level, 25, 30 liters a minute for two and a half, three, four hours, it starts overstretching the muscles in the atria and the right ventricle particularly, and it leaks into the bloodstream. And again, you know, like I 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 catecholamines and high levels of free radicals that are now unbuffered. And so if you're designing, like I like to talk about, training for longevity is very different than training for peak exercise. And a car buff like, you can understand that. It's like, if you're going to build a Formula one 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, you know, a Honda Accord that you're driving. Never more than 70 miles an hour, and you keep and maintaining it really well. And so 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.

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 want to reiterate what you said. If your goal is to win the Ironman 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 Ironman, 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 Ironman is going to take, or frankly even somebody who comes in under 10 hours.

But swimming the Catalina Channel in the dark in ten and a half hours, that is also a pretty remarkable feat. That's way beyond what a normal person is 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, like a time trial. But there's something about the Ironman 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 or 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 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 you 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, it's a, it's a bonding experience and there's a lot good about that. But I'll just interject my, my transitions because I kiss. I played basketball, you know, competitively, 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 to me, I made this mental note when I stopped playing varsity basketball, that I would exercise pretty much every day because I knew it made me and healthy. So then I kind of got into running, then triathlons, and I did short, you know, like 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, went in like sprint distances, you know, in 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 also in the back of my mind, being a cardiologist, you know, sort of thinking, being proud and happy that, you know, that I'm 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 ectopy, some PVCs or some PACs or two or three runs in a row of PACs or supraventricular tachycardia. And I thought, you know what? My heart is not happy about this, you know, and. And it disturbed me a little bit. And I kind of checked with cardio scan. I had a little bit of calcium 21. But then I started thought about it. I thought, you know, this is. Makes no sense. I mean, I'm thinking that if some exercise is good and moderate exercise is better, that extreme exercise is not 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, 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 Schnorr and Copenhagen, putting together some databases and, and showing that in fact, and this is there in plain sight all the time. By the way, Pathenbarger, one of the godfathers 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 10 years. But in the extreme deciles, it's just a small group of people who are doing the most exercise per week actually lost like 38% of, 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 Hippocrates2500 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 2,500 years ago, they, they recognized that it's not going to be sedentary, 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 going to 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 retired professional cyclists and you compared them to age matched controls and matched them in any way possible, these professional cyclists were seven times more likely to have atrial fibrillation. Is my memory serving me correctly or am I out there to lunch on that?

No, that's almost spot on. But also I point out that 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, like into middle age and beyond are the ones. I see these people all the time because I've written about this a lot. I see patients all the time come in with AFib and it's like 700% increased incidence of AFib, which is a really common part arrhythmia, where the atrial, where the rhythm arises, becomes disorganized and chaotic. And so it, it just scoots through the AV node through into the conduction system, down to 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 catecholamine 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 little micro islands of fibrosis in the myocardium, 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. And AFIB 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'd 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 just to become a runner. He went down to northern Mexico and ran with this tribe that has its runners in it, the Tarahumara Indians. And he would run just remarkable distances and became sort of like an example of any 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 on him and he found this, you know, dilated, scarred up heart. Just what we were 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 fit. 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 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 and things like that. But yeah, I'm not a big fan of these extreme. And there's more. I have a friend who, who did the seven marathons in seven days on seven continents race. Megan. She's a really, she's a good friend. 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, although she's kind of cut back on it. But if you measured what's going on with her heart during those times, I mean, 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 though they're prospective, they're 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 nonlinear. 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 have 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 troponin acutely. And if you keep them 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 that plateaus off in the middle and at the very end it fish hooks up. It's like diet. And so you're not going to be able to prove it because these are lifelong patterns that, that emerge. And it's impossible to randomize people too. But you know, there's a lot to be said for The N of 1, you know, you're paying 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 about like the best kinds of exercise. Because this, this friend of mine, Peter Schnorr and Jacob Marat, 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 focused, kind of like the Framingham Study was in America for diet and lifestyle. This was like the Framingham Study for exercise. They sort of collected a lot of data about what people were doing for exercise and then followed him through the decades. And you know, the people in Copenhagen, I think it's the city in 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 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 collected data on eight or nine specific sports, including running, swimming, cycling, health club activities, which included treadmill and all the stationary exercise machines with weight that put all that together. And then there was tennis, badminton, soccer, golf I think were the ones. And so we sat down, we'd done some other analysis, this data showing that it was the moderate dose runners that did the best for longevity during the four decades Long follow up of that. But this was a more, this was a different look at it. And, and so we said what sport is best for conferring longevity? And so, you know, they did all the multivariable analysis for, because, you know, tennis players are different than, than maybe cyclists or whatever, but quantitative how much exercise per week and maybe, you know, this data. But, but what do you think? I know, it's just shocked me. I went over there to, to finally look at the data and we were sitting around a coffee table one Sunday afternoon having a glass of wine and talking it over. And he sort of reveals this data to me and I look at it, you know, it's multi variable adjusted data. And I was really like speechless. I was just, it just, I just thought, 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 added life expectancy, health club activities on the one and a half year life expectancy added and those social sports, badminton, tennis, golf. I mean, it's easy to imagine soccer, but we're like six to ten years added life expectancy, multi variable. And I just thought, well, it's not even since 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 Holt Lumstead, that said the single best predictor, better than smoking or diabetes or exercise or blood pressure lipids for conferring longevity was strong social support. You know, relationships are the key, and you kind of instinctively would understand that. But then I started thinking, well, you know, particularly for us sort of like emotionally challenged gender, you know, males, it's like we make friends at work 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 confer best longevity and they're also the ones that sort of promote more social activities. So 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 played as kids, we need to be playing as adults even more because it's so important not only for social bonding, for stress relief, for antidepressant. 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 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 realize that if we were going to treat everybody in that gym as one cohort of everybody who goes to the 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 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 effect of, 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. Well, 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. And 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.

Balance.

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? I just sort of laid out mine.

Well, yeah, you're right on as usual. If you're spending a lot of time, say, running, I know a lot of patients who run horse 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 you're, yeah, you're getting your, your aerobic fitness really high, but, but it's not great for your skeleton or your, you know, or your balance or. I mean, 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, you know, sexual activity, if nothing else, is exercise, 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 try to figure out the area under the curve for 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 of really high intensity exercise is just not. I just don't think it's the ideal approach to fitness.

There was a podcast I did with Indigo San Milan where we talked very specifically and in great detail about Zone 2. Zone 2 being defined as this area where you have the maximum efficiency of the mitochondria. So you're able to keep lactate systemically below 2 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 oxfos. For most people, that's a lower level of activity than they're used to. You know, 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 kind 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, 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, so what should my heart rate be, what's my training zone? And all that kind of stuff. But for most people, I tell them I wouldn't pay much attention to your heart rate except for the fact that I love activity trackers and they could track the pulse and stuff. But I think the most important parameters about pulse are what your resting pulse is. We want to get that nice and low. 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 trying 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 are less than 4,000 steps a day, people who are 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 the peak. I mean it plateaued there above that, it didn't go down further, but there was a 67% reduction in mortality. So like you can get pretty much the full benefit exercise with just a lot of steps and most of those being walking. I would agree that you want to add some higher intensity interval, but it doesn't take a lot. I mean like if you look at running, 5 miles of running a 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 nadir. 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 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 and 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 disease 6 sinus 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, 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, you know, your buddy you're working 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, it runs, you know, 42, 44 most nights. And if I get over trained or underslept, I've been on call, been under more stress, been traveling too much, it'll start raising up to, you know, 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, like a cardio protective zone. And it involves the right amount of exercise and the right amount of sleep and not too much alcohol and some, you know, plenty of downtime and play and those sorts of 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 a 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 want to 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 going to be 55 one day?

55. Only if they get really serious about say 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?

Oh, absolutely. And of course it goes along with their waistline coming down and their blood pressure coming down and their triglycerides lower and their A1C lower. So you know, 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 like paid attention to in my diet and you know, back when I was in medical school in the 80s and my training in the 80s and, and you know, that was the time when, you know, the Pritikin 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, and I was getting skinnier and you know, my athletic times weren't better and in fact they were worse and I wasn't feeling that good and 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 go out to eat friends, we'd be eating pizza and I'd take off the toppings and just eat the crust, you know, and then, and then for a while then I kind of got into the sort of keto phase and I would eat the toppings and throw away the crust and I figured, yeah, pizza probably just not worth eating at all. So, you know, and I did lots and lots of white rice and you know, and try to minimize fat. And then I realized, you know, you can't generalize for one thing. That's a disaster for, and it's played out on a, on a population wide level in America. That kind of diet makes us fat. Belly fat, triglycerides are up, 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. With intermittent fasting as the omnivore's solution to the omnivore's dilemma of what to eat. And we think if you put together 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 to 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 predimed study, which I'm sure I've discussed in great detail on a previous podcast, though unfortunately I can't recall hopefully in 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 I think the findings of that, though they needed a revision based on an error in 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 wrote. And Emilio and I have been working together on a lot of projects recently. But it was the Mediterranean diet versus the American Heart association diet, which is that diet that we were just dissing. That's the low fat trending towards vegetarian diet that's high in carbs. But that showed in this group of 7,500 people, followed for 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 and the other half got mixed nuts, tree nuts that were almonds, Walnuts and filberts or hazelnuts. So they were adding fat in the case of the nuts, you know, vegetable protein. And when you, when you do the multivariable analysis on what correlated best, it was the added fat. It didn't increase saturated fat, but it increased these healthy fats from these healthy foods. And as Emilio likes to point out, with the olive oil, 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 stinging at the back of your palate. You need to, every time you open a bottle of olive oil, because it's not on the label, generally the polyphenol content, you taste it and it should have this burn 10 or 20 seconds after you swallow it in the back of your palate. Those are super important antioxidants 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 decades, Dr. Vogel and his colleagues did a study showing that olive oil was bad for your endothelium. And that never made sense to me. And then I realized, oh, they were using like an antioxidant depleted, not one of these high polyphenols, antioxidant olive oil. 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, if they go to 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 pure extra virgin olive oil or anything but, and I don't know how they get away with it, truthfully, 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've somehow managed to lie their way into saying it's pure olive oil. So you have to be careful of what you buy.

But because of those, because of that prediment study though had the intervention of extra virgin olive oil or nuts. I mean, we have a rare thing, by the way, as you're always pointing out, we have first level randomized data showing that adding this to the diet will reduce heart attack, stroke and cardiovascular death. These are delicious foods when you get used to eating them. And 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 salmon. It's only 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 Mediterranean diet. These weren't. These weren't Mediterraneans who are living high on the hog. These are the peasants who were growing their own vegetables and tending their own olive garden and their own grapes and the red wine and that sort of thing.

So, 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 refined carbohydrates, 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, when people ask me about what's the most important thing on the diet, I don't mention getting rid of red meat or getting rid of saturated fat. I mean, a moderate amount of that is, again, our evolutionary history. 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 going to kill you. You know, really, like, 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 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 fat is 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 in 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. I know you've written about not just salt, but also magnesium. And that's something that's also really near and dear to, 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 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 2 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 we're getting like, and fiber is 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 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 mineral. I mean, it's an important cofactor for a lot of the most essential sort of chemical reactions going on in our body. Magnesium is. So it's really important. But it's also makes me think that 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 squirrel or whatever, and they would cook it, or buffalo for that matter, they'd cook it. They would eat nose to tail, right? They'd eat the whole thing. These days when we eat meat, we usually eat muscle meat, which is a very narrow sort of range of animal based nutrients. One of the things when you eat nose to 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, too, a bunch of collagen. You get calcium hydroxyapatite, which is a form of calcium that we're meant to eat. We weren't meant to eat rocks, which is the standard calcium supplement. It's calcium carbonate or calcium gluconate. Those are 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, a gram a day of calcium from there, and then. And your magnesium, I would agree 2 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 give. A 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 in our 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 4 heart failure and bad kidney disease and whatnot. And there you have to do be somewhat careful. But I virtually never tell people to do that. Less than 1,500 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, like, the. The listeners here and these 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 consult it to make it taste good. And when you add salt to those natural or lightly salted nuts, I mean, you don't need to worry about that. That's good for you, having some salt in your diet when you're eating an otherwise naturally healthy whole 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, you know, is a diabetic drug that blocks this sodium glucose co transporter in the tubule in the Nephron. When we filter our blood through the Nephron, through the kidneys, we pull out a lot of things, your water, sodium toxins, urea, including glucose. And then because the body is saying there's no reason to waste this glucose, you know, we need these calories. So it reabsorbs the filtered glucose before the urine goes out. So we figured they engineered a drug to block the reabsorption of that glucose that's filtered. And when this drug, when these classic drugs first came out seven or eight years ago, I'll have to tell you, Peter, I thought this is a dumb idea. I mean, everybody knows that glycosuria is terrible for the kidneys. And this is like it, maybe lower sugar, but in the long run, it's going to be. But that's the beauty of science. That's why you do these big randomized placebo controlled trials. And when the first one came out, the EMPA reg study about five years ago, my phone and text mess 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, that controlling sugar prevented cardiovascular death. And we couldn't prove it, shockingly, until this trial came out. And it reduced cardiovascular death 38%. It reduced heart failure, renal failure. I mean, it was just an amazing thing. And subsequently, there's been, Oh, a good seven mega trials now, you know, between 3 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 lowering sugar, 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 may have something to do with ketones. But the most shocking thing about this that's really blowing the lid off this 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 its efficacy in 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 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 we'll get better and better answers churning away.

And you know, but so it's so fascinating to think about how this works. And I don't prescribe metformin for people without diabetes. I mean it upsets your 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. I mean it raises ketones in your system because of the fact. And it does tap into belly fat. It taps into belly fat to get the fatty acids that then turns in the liver, turns into ketones. And we still don't fully understand how it works, but it's an important drug class that, 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? So seven years ago, that was my thinking, 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 groin regions, on the genitalia. And, you know, when you think about it, you are putting sugar in water in warm, moist places. So I tell people on an SGLT2 inhibitor, then you don't, you know, pay special attention to use a wet wipe after urination, especially females, because there's 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 pyelonephritis or urosepsis. So it may be just that it's making the system otherwise healthier. You know, your immune system, your kidney function, your cardiovascular 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 2 diabetes and postprandial glucose.

This is the key issue, okay? And you know, the answer to this is that insulin is the problem. Insulin is a 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, fats and glucose into cells to be burned. Or if you're not burning, you're not in a burning mode right now. You're not exercising, you're sitting around sleeping. It stores them as 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 prednisone, they will get belly fat like crazy. And I always felt sorry for these diabetics. You know, the endos would be putting them on all this insulin. I'd be telling them, 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 atherosclerosis. You know, high insulin levels. The key is low. You want to, you want to drive your insulin levels as low as, like your pulse. You want a nice low insulin levels. They go up when you eat and then they 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 easily digestible, refined carbohydrates. You eat a lot of fiber, a lot of low glycemic fruit, but more, more, more sort of non starchy 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, nuts and olive oil and avocados, guacamole and salmon and sardines and trout. And you will have you know this from wearing a glucose monitor. I've worn a glucose monitor for a while too. Being non diabetic, I found it a really great behavior 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 putting on belly fat. We wrote an article called, you know, insulin is a cardiotoxic medication. I mean, we want to minimize the amount of insulin. Fortunately, these new drug classes, SGLT2 inhibitors, GLP1 agonists, that's semaglutide, dulaglutide, there's a couple others. These two together along with metformin for diabetics amazing drugs, they all lower insulin, they all reduce fat, belly fat, and they all improve cardiovascular prognosis. And by the way, a lot of it has to do with the effect on insulin.

Tell folks how the GLP1 agonists work. We might as well round out that trifecta.

Yeah. So GLP1 agonists 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 glucagon production in the liver cell phone. You're making less glucose gluconeogenesis when you don't need to be. And that's part of the problem. When you're eating this chunky diet, you get these incretin levels 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 postprandial insulin. And incretins also slow bowel motility so that it slows absorption so you don't get the big spikes in glucose and actually kind of makes you feel full faster. So these are wonderful drugs for weight loss I'm using on some of my patients now. High dose semaglutide and it'll lose up to 10% body weight in a very safe way. I mean even in non diabetics, very safe way to get your weight down. And I'll combine it with SGLT2 inhibitors and non diabetics it works, it reduces cardiovascular risk. People on GLP1 agonists tend to complain of some when you first started and when you dose titrated 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 one of them. Liraglutide is Sextanda, but it's a once a day drug. 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 milligrams rather than 1 milligram for the top dose. And it's shown it's just best ever weight reduction. And it's Sort of an alternative to bariatric surgery for these really overweight patients.

Wow, I didn't realize that. So you're telling me that you can now take. Take a GLP1 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, better cardiovascular reduction. It reduces heart attack, stroke, cardiovascular death better than the daily one, the liraglutide. 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 stronger effect on MI stroke. And you know, those ruptured plaques we were talking about at the beginning, they cause weight reduction from two different mechanisms of action. They improve cardiovascular prognosis from two different mechanisms of action. And they really work well together them. 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 would 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'm. That I'll use in patients. And I. Every physician, I think, who prescribes these has their own little secret alchemy around it. You know, when they're using Livalo vs. Prevastatin vs. Crestor vs. Lipitor, et cetera. But let's talk broadly about them as a class. So 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 want to 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 you. 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.

The latest pleiotropic effect, if you will, on statins is there was a study just this week came out that people who are on statins seem 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 more 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. I'm always arguing with my patients about statins and they'll say, have you read about these things on the Internet? And I point out to them, in the history of science, in the history of medicine and randomized trials, there's never been a class of medications that have been so thoroughly tested in gold standard randomized placebo controlled trials lasting up to years. There's like 500,000, half a million people in various randomized trials showing that if you have heart disease or especially if you've had a cardiovascular event, they will help improve your prognosis. They reduce mi, stroke, cardiovascular death, probably all cause mortality in 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?

Yeah, 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 score. And when you, when I was working out hard, like I wouldn't, like my muscles would hurt harder, you know, I mean like they would ache, they would ache worse after a hard workout. And then so I started taking coenzyme Q10 and switched over to, you know, a more of a less potent one and sure enough, they got better. So they frequently are associated with these nuisance 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 sort of the nocebo effect, the voodoo effect. They read about this and there's all sorts of people trying to capitalize on selling people alternatives to statins. That being said, I argue with people about statins who really need this. The 55 year old just had an MI who tells me, I'll do Anything but take a set. And fortunately, now we do have other good options. Ezetimibe lowers cholesterol by reducing absorption by blocking the Niemann Pick receptor. And PCSK9 inhibitors, which just prolong the life of the LDL 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 to Dr. Dayspring about that and I completely agree. So we have an option for those people who are statin intolerant because ezetimibe and PCSK9 inhibitor, they work synergistically like statins and PCSK9 inhibitors or ezetimibe and statins. But for people who have a zero calcium score, who are at relatively low risk, we do the Mesa risk calculator or the ASCVD 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 in them I say, you know, let's not get overly shook up about your LDL and let's just, you don't need your statin, we can stop your statin, we don't need to start it, whatever. And we'll focus on diet and exercise and lifestyle. But in middle aged people, I need to see that, that zero calcium score or a low calcium score to do that. But yeah, statins are a wonderful tool. They're cheap and we use a lot of them. But, but we also stop a lot of them. And, and I think for. I'd be fascinated to hear this. I 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 Dayspring that to the extent that statins do sort of impair a cell's ability to make cholesterol, it does that not only in the liver, that makes the most of cholesterol, but it does that in the brain. And people say it doesn't matter about getting cholesterol too low because cells can. If your brain makes its own cholesterol, cholesterol, if it does, if it needs it, if it's not poisoned, the HMG isn't poisoned 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 demented people, they have lipid depleted brains, you know, it's shrunken brain. I mean, there's a good study showing that omega 3 helps to keep your brain plump. A high, high omega 3 diet. And for that same reason, I have some, some sense that we might be better off using non statin approaches to lowering cholesterol like PCSK9 inhibitors, omega 3, ezetimod, 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, desmosterol and lithosterol. 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 desmosterol and orthosterol in the presence of statins may be a predictor of increased risk. And we just, in that situation, based on all the reasons you've laid out, play to the precautionary principle. And frankly our application of that is there's probably only two patients in my entire practice that are going to walk around with a desmosterol 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 Zetia. And I think physicians are becoming more liberal with that, which I think is great. Coupled with frankly, prevastatin is 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 say atorvastatin or pravastatin will. And it doesn't increase risk of type 2 diabetes. And when you use it with Ezetimibe, which again we have a great study, the Utopia study in primary prevention. Ezetimibe reduced Cardiovascular events by 30%. And then we also have the improvement study that showed that if you combine it with a statin, it reduce cardiovascular events. So we have really good first level evidence about ezetimibe.

But the only thing I would disagree with you on and disagree might Be too strong a 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 a person 10 year risk is 2% and their calcium score is zero, but their APOB 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's, 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 at least I don't know of third year risk calculator. So that that calculator you're using is in your head and you know, that's sure 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 statin. I haven't for years. I don't have a lot of risk factors, but it did have a little bit of calcium when I checked it years ago. So I'm sure I have more now. Statins will accelerate coronary calcification, by the way. So I use ezetimibe with a PCSK9 inhibitor in myself because it doesn't have any side effects. Neither of 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 wherever. This is just sort of making you as if you were genetically one of those gifted people that 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 from Prevastatin over to Tazetia to see and the reason for me is I had a calcium score of 6 when I was 36. And that's in the presence of 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 adage. If you run the engine hot enough, you can burn any fuel. But Peter, I would say you said kessem score of 6 when you were 36, despite your exercise. I would say maybe because when you're swimming 20 miles overnight, you were hammering, hammering. And really intense exercise will accelerate coronary calcification.

Yes, I have actually thought about that. And I repeated the calcium 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, calcium scores that are super rare, 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 radiologists in New York City. And, you know, so I had a CAC and CTA done with them. Incredibly low radiation, by the way. 2.2 millisieverts 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? Were you just sort of missing it? Because there was still a little blip in the endothelium 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 hack 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 but 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, like the compound interest, it really can accumulate. And I'll have to say I've probably read 150,000 calcium scores in the last 20 years and we've probably done 600,000 in our practice and we do 50 or 60 every day. So like, you virtually never see that. And now granted, at that low level, you know, you kind of nipped it in the bud with your better diet and, you know, probably, you know, 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, you know, decades at a calcium score of like 1200. They've been going up. No diabetes, but, you know, he's obese. And we switched him over because I have some eggs to a PCSK9 inhibitor and azetamide and a calcium score a couple, three, three years later had gone down from like 1200. I mean, from. No, it was like 1400, but it was like 2 or 300 lower, you know, more than the margin of error of the test. That made me think, you know, well, number one, statins do tend to increase coronary calcification, But I bet PCSK9 inhibitors don't. And certainly that anecdotal experience, and I'll bet you Ezetimibe doesn't either.

So I saw an abstract, but I don't know if it ever made it to 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 rescanning you next year to find out you're 120 versus 80. It will not change our management and.

It just discourages somebody who's doing their best. It's very discouraging to think and then you have to explain, well, well, you're on a medication that does accelerate it, but it reduces your risk despite that because it's making the plaques less prone to rupture. And I'm the same way. I rarely. The only time I increase it is 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 1000 to 1300 or 100 to 200. 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. And were talking about despite the coronary calcium.

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, our cardio wellness clinic. We have two different clinics, one focusing on the glucose side of things and the SGLT2 inhibitors and the GLP1 agonists and metformin and weight loss. And the other one on is just standard risk fact of lipids and whatnot. But we get them plugged in. We see them two, three times a year. We make sure they're. There's nothing like feedback, Right. I know you're a big fan of getting lipids tested and test these various markers, HSCRP A1C, a lot of things that 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 pharmaco level, 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, you know, super enlightened question, and this is like one at the crux of some of the most exciting stuff going on right now. So Omega 3, like we were talking about some other nutrients, we're eating like maybe an order of magnitude less of that than what we did in our evolutionary experience. Some people argue when we get access to shellfish and seafood is when our brain expanded 3 or 400,000 years ago. So the omega 3, 20% of the dry weight of the brain is polyunsaturated fats. And its favorite polyunsaturated fat to plug into those membranes in 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 is even randomized controlled 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, and these big meta analyses, not to mention the Reduce it study which recently tested the 4 grams of EPA and people who had heart disease or diabetes with other risk factors. You test triglycerides above 150. 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 distrust 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 Mayo Clinic proceedings coming out this coming week. I wasn't on this, but one of my best friends was Chip Levy from down in Ochsner. 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 mi, cardiovascular death and even trends towards all cause mortality. But the point is like a lot of the Studies just use 1 gram, but if you use 2, 3, 4 grams, you see these really remarkable, like in the reduce it 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, for the membranes. And our evolutionary experience would suggest we weren't just eating epa, we'd using the combination.

I'll tell you, I agree with you completely on that. And 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 4 gram EPA VASPA trial trial. So again we just have to see where this thing goes.

But I agree with the strength trial you were talking about.

That's right. That was halted early. Yeah. So it might be that 4 grams 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. I think 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 an over the counter version 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 Cardiotabs that we, you know, I, 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 the leaders in that 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, 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 markedly improve mental health. My wife Joan is 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, off of antidepressant medications that, and like a well absorbed curcumin with high dose omega 3 is as good as anti or better than any antidepressant out there and they also help 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 I sent you a copy of in the Journal of Alzheimer's Disease showing that a highly absorbable curcumin, Theracurmin, in a randomized trial. The study was 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 sort of systematic review, that the biologics that reduce TNF alpha, like etanercept is the best one. It's this decoy receptor for TNF alpha. And so it reduces inflammation. And there's multiple big studies of millions of people in databases. That's all observational data, but that it reduces risk of Alzheimer's disease 60 to 70. Now those are expensive biologics that sometimes can cause serious side effects. But curcumin is the active ingredient 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, preventing Alzheimer's disease. And it still needs to be fleshed out, but there's some very good biological plausibility behind it and some fascinating animal data, human data and even some small randomized trials.

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 is which we define as age over 60, a relative that has a history of Alzheimer's disease, or at least one copy of an APOE4 gene or some other gene, such as an anti TNF gene or Tom40 or one of these other genes that tends to be associated with Alzheimer's disease, plus or minus APOE 4. We just have sort of a full court press approach. And one of the things on that list is indeed theracumin 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, as was 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 mean, I think that the people who are best informed on that would agree with you on that approach.

I guess closing thought, James, is I'm just impressed by the breadth of your sort of curiosity and obsession. Again, interventional cardiology is a niche sport, right? 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 theracumin can play in inhibiting tumor necrosis, factor in the development of dementia. I, 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 this gift of we have our time here on Earth and it's about helping others and, 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. It 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, you know, suffering 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, 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 said it at the outset. Nobody's reimbursing really for prevention. You've gotta 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, that's a difficult question, but I can just tell you that it doesn't have to be all or nothing. You know, even like the calf jockeys, like they say, you know, some of my partners are, who are calf jockeys who are very enlightened about lipids and, you know, don't necessarily have to do it all the time, but you need to be a Will they be well versed enough to strongly endorse it? And I mean, I'm in a big group of 65 cardiologists with another 50 nurse practitioners or physician's assistants, and so I can kind of carve out that niche and live there most of the time, although I still round in the hospital and that sort of thing. 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 there'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.

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Sam.