The Peter Attia Drive
#334 - Cardiovascular disease, the number one killer: development, biomarkers, apoB, cholesterol, brain health, and more | Tom Dayspring, M.D.
Mon, 03 Feb 2025
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Tom Dayspring is a world-renowned expert in clinical lipidology and a previous guest on The Drive. In this episode, Tom explores the foundations of atherosclerosis and why atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide for both men and women. He examines how the disease develops from a pathological perspective and discusses key risk factors, including often-overlooked contributors such as insulin resistance and chronic kidney disease. He breaks down the complexities of cholesterol and lipoproteins—including LDL, VLDL, IDL, and HDL—with an in-depth discussion on the critical role of apolipoprotein B (apoB) in the development of atherosclerosis. Additionally, he covers the importance of testing various biomarkers, the impact of nutrition on lipid levels, and the vital role of cholesterol in brain health, including how cholesterol is synthesized and managed in the brain, how it differs from cholesterol regulation in the rest of the body, and how pharmacological interventions can influence brain cholesterol metabolism. We discuss: Defining atherosclerotic cardiovascular disease (ASCVD): development, risks, and physiological impact [2:45]; The pathogenesis of ASCVD: the silent development over decades, and the importance of early detection for prevention of adverse outcomes [10:45]; Risk factors versus risk markers for ASCVD, and how insulin resistance and chronic kidney disease contribute to atherosclerosis [17:30]; How hyperinsulinemia elevates cardiovascular risk [24:00]; How apoB-containing lipoproteins contribute to atherosclerosis, and why measuring apoB is a superior indicator of cardiovascular risk compared to LDL cholesterol [29:45]; The challenges of detecting early-stage atherosclerosis before calcification appears [46:15]; Lp(a): structure, genetic basis, and significant risks associated with elevated Lp(a) [55:30]; How aging and lifestyle factors contribute to rising apoB and LDL cholesterol levels, and the lifestyle changes that can lower it [59:45]; How elevated triglycerides, driven by insulin resistance, increase apoB particle concentration and promote atherosclerosis [1:08:00]; How LDL particle size, remnant lipoproteins, Lp(a), and non-HDL cholesterol contribute to cardiovascular risk beyond apoB levels [1:21:45]; The limitations of using HDL cholesterol as a marker for heart health [1:29:00]; The critical role of cholesterol in brain function and how the brain manages its cholesterol supply [1:36:30]; The impact of ApoE genotype on brain health and Alzheimer's disease risk [1:46:00]; How the brain manages cholesterol through specialized pathways, and biomarkers to track cholesterol health of the brain [1:50:30]; How statins might affect brain cholesterol synthesis and cognitive function, and alternative lipid-lowering strategies for high-risk individuals [1:57:30]; Exciting advancements in therapeutics, diagnostics, and biomarkers coming in the next few years [2:09:30]; Recent consensus statements on apoB and Lp(a) from the National Lipid Association (NLA) [2:12:30]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
What is atherosclerotic cardiovascular disease (ASCVD)?
But two things, their protein content, over 150 proteins have been found to be associated with various HDL particles. And they perform an immense number of likely very necessary actions that need to go on in certain tissues where things may be going wrong. We also know that the coat of an HDL, apart from its proteins, is virtually all phospholipids.
So the exact phospholipid concentration of an HDL surface has tremendous amount to what to do. Can an HDL do wonderful things or bad things? Those phospholipids really determine what an HDL can bind to in various tissues. Now, of course, we can't measure HDL phospholipid content. There are hundreds of phospholipids.
You would get a lipidome coming back that you couldn't even pronounce half of the phospholipids or at least the fatty acids that are in those phospholipids. And same with the protein. If there's 150 of them, I guarantee the average doctor might be familiar with about 10 of those proteins and not with the rest of them. So I don't know how to determine a patient's HDL functionality.
Clearly, the people having adverse effects with high HDL cholesterol have dysfunctional HDLs probably related to that proteome or their phospholipid content and vice versa. So what we tell a person right now is in the year 2024, we didn't always believe this. This bad cholesterol had an origin that everybody believed way back when.
Framingham, Mr. Fit, the earlier observational trials, nobody ever adjusted for ApoB in those trials. It wasn't even available when they were doing it. So we now know that the people with low HDL cholesterol who do get atherosclerosis always have high ApoB. And why? Why do those people have low HDL cholesterol? I've already told you it's the trigs that knock the HDL. And the trigs may not be 400.
The trigs may only be 130, which are being ignored. and what is high in them, ApoB. So the proper treatment of low HDL cholesterol in the person you believe has cardiovascular risk is just like trigs, lower ApoB, lower non-HDL cholesterol if you can't get an ApoB. If somebody has a high HDL cholesterol, I don't know what blood test to tell you. I would always check an ApoB.
We do that in 100% of people. And if it was high, we would treat ApoB regardless of an HDL cholesterol level. But I can't look at a man or a woman and say, oh my God, you're the one with high HDLC who might wind up with dementia or some cancer or something. I don't know. So we'll track those other diseases with other modalities that we have at our beck and call
I don't know what to tell you about your cardiovascular health if you have high HDL-C, but I can guarantee you it is not a declaration of cardiac immortality. So it's HDL functionality.
And you recall we had a nice email exchange about a friend of mine who I've known for many years. He's always had a very high HDL cholesterol and a very low LDL cholesterol. In fact, his HDL has routinely been above 100 milligrams per deciliter, and his LDL cholesterol has always been below 100 milligrams per deciliter. So this is a guy that by anybody's metric looks like he's in tip-top shape.
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