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Tom Dayspring, M.D.: The Latest Insights Into Cardiovascular Disease And Lipidology | The Drive with Peter Attia #129

Key Takeaways

  • Atherogenic lipoproteins are now widely recognized as the driver of atherosclerosis
  • Smoking and hypertension are two of the biggest risk factors for cardiovascular disease
  • “The causal relationship between apoB and atherosclerosis is as strong as anything we see in medicine.” – Peter Attia
  • The overwhelming majority of people with low HDL have a high apoB which drives atherosclerosis
  • Lp(a) represents the single greatest driver of atherosclerosis
  • Everyone should be tested for Lp(a) once in their life
  • Statin contribution to atherosclerosis reduction is likely because of apoB reduction

Introduction

Tom Dayspring, M.D. (@drlipid) is a world-renowned lipidologist and chief academic officer for True Health Diagnostics, LLC.

In this episode of The Drive, Tom Dayspring follows up on his 2018 five-part series and provides an update on the current events in lipidology including topics such as atherogenic lipoproteins, apolipoprotein B (apoB), lipoprotein(a), risk assessments, and much more.

Host: Peter Attia (@PeterAttiaMD)

Updates To Clinical Practice And Guidelines Since 2018

  • Atherogenic lipoproteins are now widely recognized as the driver of atherosclerosis
  • Atherogenic lipoproteins are diagnosed using cholesterol metrics
  • New understanding of what contributes to atherogenicity of apolipoprotein B (apoB) particle and how glycerides affect lipoprotein concentration and function
  • Risk assessment has been modified
  • Recognition that HDL is not a terribly valuable metric
  • Emerging significance of lipoprotein(a) (LP(a))
  • Pharmacology has advanced

Brief Refresher: Lipids Apoproteins, And Apolipoproteins

  • Lipids are hydrophobic so must attach to protein to move
  • Collections of lipids attach to proteins which allow them to be soluble
  • Apoprotein = proteins that wrap collections of lipids  
  • Apoproteins provide structure and stability to lipoprotein

What Is apoB?

  • Apolipoprotein B (apoB) is the main structural protein that lipids throughout the body
  • HDL particles are the second class of lipoproteins
  • HDL has no apoB – their structural protein is apolipoprotein a1 (APOA1)
  • Two classifications of lipoproteins: apoB lipoproteins called beta lipoproteins; APOA1 lipoproteins called alpha lipoproteins
  • The liver and small intestine make apoB lipoproteins
  • apoB family: LDL (low-density lipoprotein), VLDL (very low density lipoprotein), IDL (intermediate density lipoprotein), and Lp(a)
  • 90-95% of apoB particles are LDL particles (LDL-P)
  • Pick your favorite metric and stick with it – don’t switch from measuring apoB then LDL-P and back – consistently use biomarkers

apoB Concentration Matters

  • Smoking and hypertension are two of the biggest risk factors for cardiovascular disease
  • Smoking and hypertension weaken the endothelium
  • apoB-bearing particle in the presence of injured endothelium drives destructive trajectory of cardiovascular pathology
  • “The causal relationship between apoB and atherosclerosis is as strong as anything we see in medicine.” – Peter Attia
  • We need to know particle concentration and quality of lipoproteins
  • Researchers are working towards discerning what other components of lipoprotein and particle concentration lead to pathology in one person compared to the next

Cholesterol, HDL, And The Problem With Our Metrics

  • All the cholesterol circulating in the body is either in the brain or in plasma
  • Red blood cells carry more cholesterol than all lipoproteins combined
  • Histology (tissue composition) of red blood cells prevents them from being the primary diver of atherosclerosis
  • The amount of cholesterol in lipoproteins doesn’t correlate to cellular cholesterol or red blood cell cholesterol
  • HDL cholesterol is the number you see when you look at a lipid panel
  • HDL cholesterol is measuring the concentration of cholesterol within an HDL particle
  • Cholesterol doesn’t tell us anything about the functionality of the particle or the cholesterol content of the cells
  • Virtually all risk algorithms use HDL (“good” cholesterol) as a metric
  •  “Why did HDL have such importance and now it’s an afterthought?” – Tom Dayspring
  • The overwhelming majority of people with low HDL have a high apoB which drives atherosclerosis – not the cholesterol
  • The problem with HDL as a metric is that studies were observational and never adjusted for confounding factors
  • There have been multiple trials using various approaches to raise HDL – none resulted in cardiovascular benefit
  • “If HDLs are important to cardiovascular system, which I maintain they are, the metric HDL cholesterol is useless.” – Tom Dayspring
  • The LDL biology is simple: we want to lower it
  • The HDL biology is complex and we have a crude understanding of its importance and functional relationships in the body
  • Metrics Peter Attia uses: VLDL as a proxy for remnant, triglycerides as a strategy for how to lower apoB, apoB, Lp(a), glucose, insulin, blood pressure
  • APOA1 can be misleading because there can be several molecules attached

The Significance Of Lp(a)

  • Lp(a) is an LDL carrying a damaging apo(a) made in the liver
  • Lp(a) represents the single greatest driver of atherosclerosis but not everyone produces Lp(a) in significant amounts
  • Everyone should get a biomarker test for Lp(a) – it’s a genetically determined marker and will not change so worth getting
  • One of the functions of apo(a) is as a lipid oxidizer
  • We are starting to have metrics to measure oxidized phospholipids on apoB
  • If you do have high Lp(a): lower apoB, modulate metabolic parameters
  • Lp(a) is not currently an acceptable therapeutic target
  • Pharmacologic treatment on the horizon: knock out the ability of the liver to make apo(a) then maybe we wouldn’t have Lp(a)
  • Recommended follow for more information: Sam Tsimikas, MD (@Lpa_Doc)

Statins And PCSK9 Inhibitors

  • Statins to lower LDL and apoB concentration have virtually no effect on Lp(a)
  • Statins inhibit rat- limiting enzyme in the cholesterol synthesis pathway
  • Statins should be carefully distributed
  • Statin contribution to atherosclerosis reduction is likely because of apoB reduction
  • PCSK9 inhibitors don’t have an effect on the synthesis of apo(a) in the body
  • PCSK9 has effects on apo(e) receptors and a few other lipoprotein clearing receptors 
  • Often people will end up on statin + PCSK9

Latest Understanding Of EPA And DHA

  • EPA: a new study showed 2g twice per day with food led to almost 30% risk reduction of any cardiovascular event
  • EPA + DHA is an important omega-3 fatty acid
  • EPA purists think the presence of DHA reduces the effect of EPA
  • Not everyone can convert EPA to DHA, though most can
  • “EPA or EPA + DHA? EPA 4g/day” – Tom Dayspring
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