podcast Peter Attia 2022-04-18 topics

#203 - AMA #34: What Causes Heart Disease?

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Show notes

In this “Ask Me Anything” (AMA) episode, Peter dives deep into the topic of atherosclerotic cardiovascular disease (ASCVD) —the number one killer in the developed world. Peter argues for the importance of paying attention to and understanding ASCVD given its ubiquity and inevitability. He goes into great detail about the development of atherosclerosis and how it can take hold at a very early age, the role of cholesterol, and the causal factors of ASCVD that determine prevention strategies. Additionally, he discusses the important metrics and biomarkers found in blood work, as well as diagnostic tests such as coronary artery calcium scores (CAC) and CT angiograms which help to determine the level of arterial damage present. Finally, Peter lays out the keys to understanding and interpreting calcium scores before wrapping up the conversation with his key takeaways regarding prevention.

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We discuss:

The importance of understanding atherosclerosis early in life [2:15];
Defining atherosclerotic cardiovascular disease (ASCVD), its causes, and the role of cholesterol [9:00];
The process of developing ASCVD, part 1 [15:00];
The process of developing ASCVD, part 2 [24:00];
The process of developing ASCVD, part 3 [32:45];
How early in life ASCVD can start to develop [40:30];
Case studies of atherosclerosis and figures showing real pathology [43:00];
Coronary artery lesions present in autopsies of different age groups [49:15];
The causal factors of ASCVD that determine prevention strategies [52:15];
Labs to identify biomarkers of ASCVD [59:00];
Diagnostic tests to determine the level of arterial damage present—CAC, CTA, CIMT, and more [1:00:30]
Calcium scores: keys to understanding and interpreting a CAC score and/or CTA results [1:05:15];
Is there a risk from cholesterol levels being too low? [1:13:00];
Key takeaways regarding prevention [1:15:45];
More.

The Peter Attia Drive

What Causes Heart Disease?

Show Notes

The importance of understanding atherosclerosis early in life [2:15]

Atherosclerosis is ubiquitous

It’s the only disease that is inevitable, and it limits human longevity
Cancer and dementia, also diseases of old age are not inevitable the way atherosclerosis is

“ Not everybody dies from atherosclerosis, but… everybody dies with it ”— Peter Attia

You want to understand this because the impact is huge and the tools we have are also huge
Extending lifespan comes down to delaying the onset of chronic disease, and atherosclerosis is the most common chronic disease

2 main paths to atherosclerosis

Risk factors

Smoking, a behavioral risk factor (we’ll put this aside for the moment)
1 – Hypertension
2 – High blood and lipid abnormalities (we’ll focus on this one) This leads to atherosclerotic cardiovascular disease (ASCVD)
This leads to atherosclerotic cardiovascular disease (ASCVD)

Studies of pathology show ASCVD begins at a young age

What is the most common presentation for a 1st heart attack?

Sudden death
A 1st heart attack in over 50% of people is fatal; today this number is a little less but still staggering

What is the age distribution of people who have their 1st major adverse cardiac event?

Adverse cardiac events are a heart attack or a stroke (or death)
Figure 1 shows the incidence of cardiovascular events for both males and females in the US

Figure 1. Incidence of cardiovascular events by age and sex. Credit JAMA Cardiology 2016

The graph on the right shows total annual events The 1st 2 sets of bars show the number of events for people under 65 Men are shown in the darker bars comprising slightly below 25% and slightly above 25% of all cardiac events The implication is that 50% of men who are going to have a cardiac event in their life will have it before the age of 65 For women, a third of women will have their 1st cardiac event before the age of 65
The total annual events is not the whole story; it’s important to understand how long it takes for this disease to take hold Early prevention is key
Almost 25% of these events are in men younger than 54
When you think of someone who is 45, 50, this disease didn’t start 2 years before
The 1st 2 sets of bars show the number of events for people under 65
Men are shown in the darker bars comprising slightly below 25% and slightly above 25% of all cardiac events The implication is that 50% of men who are going to have a cardiac event in their life will have it before the age of 65
For women, a third of women will have their 1st cardiac event before the age of 65
The implication is that 50% of men who are going to have a cardiac event in their life will have it before the age of 65
Early prevention is key

When you see these stats laid out, it creates a shift in your mind around why you should care about this

Defining atherosclerotic cardiovascular disease (ASCVD), its causes, and the role of cholesterol [9:00]

ASCVD is disease state characterized by the deposition or the buildup of cholesterol (sterols) in the artery wall

It begins with a fatty streak that later consolidates into plaques that can ultimately lead to a reduction in blood flow
Reduction in blood flow is called ischemia
Ischemia results in tissue damage to the heart and this is what results in a heart attack
A heart attack can be fatal depending on the amount of cardiac tissue that is damaged from loss of oxygenation

Causes of ASCVD

You don’t have to be obese or have high blood pressure

“ It’s really a question of the cholesterol in your blood. That’s really what defines the disease. ”— Peter Attia

Atherosclerosis is defined by the presence of cholesterol in the artery wall This is not necessarily related to the measurement of cholesterol in circulation
Patients with cholesterol in their arteries do not necessarily have to have co-aggravating factors such as: high blood pressure, diabetes, obesity, family history, smoking All these things that exacerbate ASCVD
This is not necessarily related to the measurement of cholesterol in circulation
All these things that exacerbate ASCVD

Cholesterol explained

Cholesterol is an organic molecule, a type of lipid It is not soluble in water It is a hydrophobic molecule Picture pouring oil into water and you would immediately see what it means to have a hydrophobic substance in contact with something that is hydrophilic (water) They repel each other
It is not soluble in water
It is a hydrophobic molecule
Picture pouring oil into water and you would immediately see what it means to have a hydrophobic substance in contact with something that is hydrophilic (water) They repel each other
They repel each other

Cholesterol is about one of the most important molecules in the body

You would die without it
Rare genetic conditions that impair the ability to make cholesterol are fatal
Cholesterol is used for 2 main things:
1 – The cell membrane of every cell in the body contains cholesterol Cholesterol contributes to the fluidity of the cell membrane, important for membrane channels that allow things in and out of the cell
2 – Synthesis of many hormones begins with cholesterol, including: cortisol, estrogen, testosterone It is also essential for the creation of bile acids, necessary to digest food
Cholesterol contributes to the fluidity of the cell membrane, important for membrane channels that allow things in and out of the cell
It is also essential for the creation of bile acids, necessary to digest food

Where does cholesterol come from?

Most people think of cholesterol as something that comes from eating certain foods This is true, eggs contain cholesterol
But the cholesterol in your bloodstream has little to do with the cholesterol in foods you eat The reason is, the cholesterol we eat in esterified, it has a chemical bond that swings between an intermediary oxygen and another side chain This cholesterol is too large for the receptors in our gut to absorb Most of the cholesterol we eat is excreted
This is true, eggs contain cholesterol
The reason is, the cholesterol we eat in esterified, it has a chemical bond that swings between an intermediary oxygen and another side chain
This cholesterol is too large for the receptors in our gut to absorb
Most of the cholesterol we eat is excreted

Most of the cholesterol we will discuss [in our bloodstream] is made in our body and transported between cells through lipoproteins

The process of developing ASCVD, part 1 [15:00]

Anatomy of blood vessels

The endothelium is a 1-cell layer that lines the surface (and protects) the arterial lumen The arterial lumen is the inside of a blood vessel; this is the area through which blood is flowing
The endothelium has really complex functions It can modulate vascular tone Remember arteries don’t stay in the same shape all the time; they can constrict a bit and dilate This plays an important role in modulating inflammatory and thrombotic processes
Tom Dayspring provided these images of blood vessels and the process of ASCVD
The arterial lumen is the inside of a blood vessel; this is the area through which blood is flowing
It can modulate vascular tone
Remember arteries don’t stay in the same shape all the time; they can constrict a bit and dilate
This plays an important role in modulating inflammatory and thrombotic processes

Figure 2 shows a small artery cut along its length; think about a coronary artery

The red part in the middle is where the blood flows along the length of the artery

Figure 2. Endothelial cells lining a blood vessel.

The coronary artery, depending on which one If it’s the left main versus a distal part of the left anterior descending coronary artery Wikipedia has a good image of the coronary arteries It may be a small as 1 mm (in diameter) or it could be as large as 4 mm
There is a single layer of endothelial cells lining the entire surface of this artery These are the tan ovals in contact with the red bloodstream
Also shown is what’s behind these endothelial cells, the other layers of the artery wall
Unlike veins, arteries have very muscular walls The muscle cells are shown as elongated cells with a dot in the center, in Figure 3
If it’s the left main versus a distal part of the left anterior descending coronary artery Wikipedia has a good image of the coronary arteries
It may be a small as 1 mm (in diameter) or it could be as large as 4 mm
Wikipedia has a good image of the coronary arteries
These are the tan ovals in contact with the red bloodstream
The muscle cells are shown as elongated cells with a dot in the center, in Figure 3

Figure 3. The muscular walls of arteries and LDL particles flowing in the bloodstream.

LDL

Figure 3 also shows LDL, the low density lipoprotein These are the multicolored balls in the bloodstream LDL is a lipid transport particle
Remember that oil and water don’t mix well; we have the same problem with cholesterol in blood
Cholesterol is essential for every cell Cells make cholesterol but not every cell can make enough to meet its own needs
Transportation in the blood is akin to transportation in water With water soluble things this is easy, like glucose or electrolytes (sodium, potassium, etc) Hydrophobic molecules are different, like cholesterol and triglycerides (fats) These molecules have to be transported in something that is water soluble That something is a lipoprotein
Lipoproteins exist in different densities The 2 most people will have heard of is the low density variant ( LDL ) and the high density variant ( HDL ) It’s unfortunate that these are called bad cholesterol (LDL) and good cholesterol (HDL) because they both carry the same cholesterol
Technically, there is no such thing as good cholesterol or bad cholesterol; it’s just cholesterol
Cholesterol does bad things when it is in a low density lipoprotein; this is why LDL got the name bad cholesterol
LDL’s zip through the bloodstream
Notice the little black line on the LDL in Figure 3; it looks like a mustache These are apolipoprotein Bs ( apoB )
Broadly speaking, there are 2 families of these apolipoprotein lipoproteins. 1 – The apoA family This family encompasses all the different HDLs (multiple) 2 – The apoB family apoB100 – This family encompasses VLDL, IDL, LDL, and Lp(a), which is an LDL with another apolipoprotein called apo(a) attached to it apoB48 – attached to chylomicrons
These are the multicolored balls in the bloodstream
LDL is a lipid transport particle
Cells make cholesterol but not every cell can make enough to meet its own needs
With water soluble things this is easy, like glucose or electrolytes (sodium, potassium, etc)
Hydrophobic molecules are different, like cholesterol and triglycerides (fats) These molecules have to be transported in something that is water soluble That something is a lipoprotein
These molecules have to be transported in something that is water soluble
That something is a lipoprotein
The 2 most people will have heard of is the low density variant ( LDL ) and the high density variant ( HDL )
It’s unfortunate that these are called bad cholesterol (LDL) and good cholesterol (HDL) because they both carry the same cholesterol
These are apolipoprotein Bs ( apoB )
1 – The apoA family This family encompasses all the different HDLs (multiple)
2 – The apoB family apoB100 – This family encompasses VLDL, IDL, LDL, and Lp(a), which is an LDL with another apolipoprotein called apo(a) attached to it apoB48 – attached to chylomicrons
This family encompasses all the different HDLs (multiple)
apoB100 – This family encompasses VLDL, IDL, LDL, and Lp(a), which is an LDL with another apolipoprotein called apo(a) attached to it
apoB48 – attached to chylomicrons

The apoB carrying lipoproteins are the ones we’re interested for this process, and of those LDL is the most important for virtually everybody

What is the concentration of LDL?

When you’re young, it’s quite low, 20-30 mg/dL of LDL in blood This LDL is simply delivering cholesterol to and from tissues that need it
LDL-C is the concentration of cholesterol within 1 particle, reported in mg/dL
LDL-P refers to the number of LDL particles, typically reported in nmol/L
ApoB also refers to the number of LDL particles, reported in mg/dL
This LDL is simply delivering cholesterol to and from tissues that need it

What measure should you pay attention to?

ApoB, the podcast with Allan Sniderman went into detail about this

Figure 4. Some LDLs have moved into the subendothelial space.

Figure 4 show that some LDLs have escaped from the vascular system and have gone into what’s called the subendothelial space, the space just behind the endothelium LDLs are slipping through the cracks in the endothelium One of the risk factors for atherosclerosis is the health of the endothelium The dominant risk factor is the lipid concentration
LDLs are slipping through the cracks in the endothelium
One of the risk factors for atherosclerosis is the health of the endothelium The dominant risk factor is the lipid concentration
The dominant risk factor is the lipid concentration

Things that are damaging to the endothelium lining blood vessels

Uric acid, discussed in the podcast with Rick Johnson
Hyperinsulinemia
Elevated glucose levels
Homocysteine

Anything that damages the endothelium is going to increase the likelihood that these LDLs can sneak their way through

Once the LDL has moved past the endothelium, there’s a reasonable chance they will get stuck there LDL binds to proteoglycans (green y’s on Figure 4) via surface phospholipids Chemical reactions can occur with reactive oxygen species that will then oxidize the LDL This doesn’t happen to all the LDL particles
HDL particles will also enter this space from time to time The difference is the HDLs leave; they don’t get stuck in the subendothelial space
LDL binds to proteoglycans (green y’s on Figure 4) via surface phospholipids
Chemical reactions can occur with reactive oxygen species that will then oxidize the LDL This doesn’t happen to all the LDL particles
This doesn’t happen to all the LDL particles
The difference is the HDLs leave; they don’t get stuck in the subendothelial space

Peter’s takeaway— retention of LDL in the subendothelial space and its oxidation is the problem and the 1st critical step in ASCVD

The process of developing ASCVD, part 2 [24:00]

Figure 5. LDL particles retained in the subendothelial space can be modified or oxidized to become toxic

The endothelial system reacts in an effort to prevent further damage
The paradox is, the efforts by the endothelium to heal itself is what ultimately kicks off a cascade of events that result in more damage
The endothelium is now dysfunctional and expresses something called selectins and vascular cell adhesion molecules These are like a 911 call to immune cells, asking them to come and repair the damage Figure 6 shows dysfunctional endothelial cells in blue expressing selectins and adhesion molecules
These are like a 911 call to immune cells, asking them to come and repair the damage
Figure 6 shows dysfunctional endothelial cells in blue expressing selectins and adhesion molecules

Figure 6. Endothelial cells become dysfunctional and express selections and adhesion molecules.

Monocytes, a type of immune cell patrolling in the bloodstream, respond to the damaged endothelium
Figure 7 shows monocytes as yellow cells with a big, blue squiggle inside

Figure 7. Monocytes are a type of immune cell recruited to the damaged endothelium.

Monocytes are type of cell that is not fully differentiated They are looking for anything that’s gone wrong in the body
The little blue hairs coming out of the dysfunctional endothelial cells are vascular adhesion molecules This will catch monocytes moving through the bloodstream These adhesion molecules increase the probability that monocytes are going to stop at this site and enter the subendothelial space
They are looking for anything that’s gone wrong in the body
This will catch monocytes moving through the bloodstream
These adhesion molecules increase the probability that monocytes are going to stop at this site and enter the subendothelial space

Cytokines elicit a systemic response to endothelial damage

These dysfunctional endothelial cells also release cytokines Shown in figure 8 Cytokines are a chemical signal that goes out to the body They elicit inflammation They initiate a systemic response to injury Examples include interleukin-6 (IL-6) and tumor necrosis factor (TNF)
Shown in figure 8
Cytokines are a chemical signal that goes out to the body
They elicit inflammation
They initiate a systemic response to injury
Examples include interleukin-6 (IL-6) and tumor necrosis factor (TNF)

Figure 8. Damaged endothelial cells release Interleukin-6 and other cytokines

Cytokines circulate to the liver where they induce the production of C-reactive protein (CRP)

We can measure all of these things, and that gives us some sense of the amount of inflammation going on

Cytokines and C-reactive protein are not cardiovascular specific They will also be elevated in a person who has an infection (even a cold) A person with a cold may have a C-reactive protein of 6-7, when the normal level is 1
They will also be elevated in a person who has an infection (even a cold)
A person with a cold may have a C-reactive protein of 6-7, when the normal level is 1

The action of monocytes in the subendothelial space is part of the disease process

Monocytes enter the subendothelial space (figure 9) and mature to become macrophages Macro meaning big and phage meaning to eat
Macro meaning big and phage meaning to eat

Figure 9. After stopping at adhesion molecules on damaged endothelium, monocytes enter the subendothelial space.

Macrophages start to ingest the modified / oxidized LDL particles The term for this is phagocytosis Shown in figure 10
The term for this is phagocytosis
Shown in figure 10

Figure 10. Monocytes ingest oxidized LDL particles

Eating these oxidized LDL causes the macrophages to become foam cells

In all of this is the body doing what it thinks it should be doing to fix a problem. This same thing occurs when you have a bacterial infection and it’s what saves your life. But here, as you can see, it’s starting to become counterproductive.

The development of pathology in the artery

When a lot of these foam cells coalesce, it starts to form something called a fatty streak Shown in figure 11 We’ll come back to this later and look at actual slides from autopsies
Shown in figure 11
We’ll come back to this later and look at actual slides from autopsies

Figure 11. A fatty streak is formed by the accumulation of enlarged foam cells.

The role of HDL

Figure 12. HDL use ABC1 to remove cholesterol from macrophages.

Remember earlier we mentioned 2 families of lipoproteins: apoB and apoA
apoA-1 particles are also known as pre-beta-HDL particles These take in free/ unesterified cholesterol from macrophages using something called an ATP binding cassette transporter, A-1 (ABC1) This means these pre-HDL particles use a suction system to suck sterol [cholesterol] out of the macrophages The ATP binding cassette transporter, A-1 uses the energy of ATP to do move cholesterol from the macrophages to the pre-HDL particles This is an effort to prevent further damage This is why HDL is thought of as good
Pre-beta-HDL particles will fill themselves up with lipids, that they remove from macrophages This particle gets bigger The HDL will take the lipids to other tissues in the body that need them Shown in figure 13
These take in free/ unesterified cholesterol from macrophages using something called an ATP binding cassette transporter, A-1 (ABC1)
This means these pre-HDL particles use a suction system to suck sterol [cholesterol] out of the macrophages The ATP binding cassette transporter, A-1 uses the energy of ATP to do move cholesterol from the macrophages to the pre-HDL particles This is an effort to prevent further damage This is why HDL is thought of as good
The ATP binding cassette transporter, A-1 uses the energy of ATP to do move cholesterol from the macrophages to the pre-HDL particles
This is an effort to prevent further damage
This is why HDL is thought of as good
This particle gets bigger
The HDL will take the lipids to other tissues in the body that need them
Shown in figure 13

HDL removes lipids from the worst place you can have them and take them elsewhere in the body where they can be used

Figure 13. HDL particles filled with lipids from the subendothelial space go back into the bloodstream to deliver these lipids to other tissues.

This is why HDL is thought of as being protective
This de-lipidation process occurs through lots of mechanisms using something called cholesteryl ester transfer protein (CETP) Notice 2 things: 1 – An entire set of drugs has been developed around CETP inhibition 2 – CETP genes are some of the genes that are modified in people who live an exceptionally long time, centenarians
Notice 2 things:
1 – An entire set of drugs has been developed around CETP inhibition
2 – CETP genes are some of the genes that are modified in people who live an exceptionally long time, centenarians

The process of developing ASCVD, part 3 [32:45]

Quick aside on the misconceptions about HDL cholesterol

It’s overly simplistic (and patently wrong) to think that HDL is good cholesterol and LDL is bad cholesterol

You can’t infer anything about risk from a high level of HDL cholesterol
Every intervention that has tried to raise HDL cholesterol pharmacologically has failed to improve outcomes This speaks to the complexity of this process
This speaks to the complexity of this process

How HDL works is complex: The functionality of the HDL particle is much more complicated than something we can assess through either their size, their number, or their cholesterol content

Back to the macrophages:

The HDLs fix some of the lipids macrophages have taken in, but in the end the macrophages become more and more engorged with oxidized LDL
The macrophages remain as full-fledged foam cells
Foam cells produce a whole bunch of things: angiotensin II, collagenase collagenases, elastases, and a whole bunch of other enzymes (shown in figure 14) This undermine the integrity of the arterial wall leading to more endothelial dysfunction
This undermine the integrity of the arterial wall leading to more endothelial dysfunction

Figure 14. As foam cells enlarge they release many molecules that contribute to dysfunction of the endothelium.

“ Everything that’s happened so far is like little break-ins in the neighborhood. We’re about to enter looting. ”— Peter Attia

What happens after foam cells accumulate?

Chemical signals start to trigger the migration of smooth muscle cells to the area of the injury
The endothelium barrier is badly damaged and has lost its capacity to do anything
Smooth muscle cells try to repair the damage by laying down a matrix to heal the injured wall
This matrix becomes the fibrous cap of the atherosclerotic plaque , shown in figure 15

Figure 15. The formation of atherosclerotic plaque.

It is only now that the lumen of the artery begins to narrow

This is pretty bad but it’s occurring before there is any calcification and before the artery wall is actually shrinking. Nothing is showing up clinically so far.

So much has to happen, years and years before you can start to see damage And it’s the damage that leads to events
By the time you’re having events, the process covered so far has happened decades earlier
And it’s the damage that leads to events

Action of enzymes released by recruited muscle cells

These enzymes that are upregulated start to dissolve and weaken the plaque cap
This typically occurs at the shoulder regions where the diseased endothelium cells meet healthy endothelial cells Some describe this area of plaque as vulnerable This may be a correct term But it also gives kind of a false sense of confidence that we can treat atherosclerosis on a lesion by lesion basis
Some describe this area of plaque as vulnerable This may be a correct term But it also gives kind of a false sense of confidence that we can treat atherosclerosis on a lesion by lesion basis
This may be a correct term
But it also gives kind of a false sense of confidence that we can treat atherosclerosis on a lesion by lesion basis

“ Atherosclerosis should really be viewed as a systemic condition of the entire arterial system ”— Peter Attia

One of the better papers on this topic is called “ The Myth of the “Vulnerable Plaque ”

Continuing with the disease process, after plaque has formed in the arteries

Figure 16. Plaque accumulates at large foam cells and starts to obstruct the artery.

Smooth muscle cells have migrated to the place of damage
The damage is greatest at the site of these large foam cells [the green blobs filled with yellow circles] This is incredibly inflammatory
The endothelial barrier is very dysfunctional and is barely holding on for dear life
Now this plaque can start to become obstructive [shown as yellow rectangles] This is how the artery narrows
Lipid rich plaques can become quite unstable and they can rupture , causing really bad things to happen
In figure 17, the plaque at the bottom is unstable Some lipid is protruding through the cap [yellow balls] If this lipid gets out, it will kick off a coagulation cascade Platelets will show up Platelets are in the blood; their job is to stop bleeding if we have an injury
This is incredibly inflammatory
This is how the artery narrows
Some lipid is protruding through the cap [yellow balls]
If this lipid gets out, it will kick off a coagulation cascade Platelets will show up Platelets are in the blood; their job is to stop bleeding if we have an injury
Platelets will show up
Platelets are in the blood; their job is to stop bleeding if we have an injury

Figure 17. The escape of lipids from plaque activates the coagulation cascade.

Platelets serve as a kind of cradle for the coagulation cascade to produce a net of fibrin [white blobs] Shown as white blobs in figure 18 This leads to a clot Red blood cells are caught in this net
Shown as white blobs in figure 18
This leads to a clot
Red blood cells are caught in this net

Figure 18. Activation of the clotting cascade leads to an occlusion of blood flow.

A nonobstructive plaque can lead to a clinical event after the superimposition of red and white thrombus This can happen very quickly This is typically the cause of a heart attack
A heart attack does not occur because the lumen narrowed little by little Typically there was some narrowing But it’s the rupture of a plaque that leads to the sudden occlusion of blood flow
This can happen very quickly
This is typically the cause of a heart attack
Typically there was some narrowing
But it’s the rupture of a plaque that leads to the sudden occlusion of blood flow

That’s why going back to what my pathology professor talked about 25 years ago, a very, very common presentation is sudden death. Those people don’t get a warning. They don’t get to say, “Oh god, I’m really having chest pain walking up the stairs today because I’m slowly losing blood supply to my heart .”

People go from being fine to dead if that occlusion occurs in a place where restriction of blood flow is fatal If it occurs at a very distal point in the blood supply, then it might not cause a fatal heart attack If it occurs high enough, it can be a “Widowmaker”
If it occurs at a very distal point in the blood supply, then it might not cause a fatal heart attack
If it occurs high enough, it can be a “Widowmaker”

A Widowmaker lesion is very, very high in the left main coronary artery. At such a level, if you occlude blood flow, you’re basically robbing the entire left ventricle of blood, which would be, universally fatal .

How early in life ASCVD can start to develop [40:30]

3 big points to remember

1 – The number of particles in the blood is important
2 – You want your endothelium to be as healthy as possible
3 – This takes a very long time to develop

How early is this happening? Is this happening at five, 10, 15, 20, 30 years old?

If we’re talking about apoB bearing particles (LDL particles), entering the subendothelial space, getting retained, getting oxidized This happens very early in life for some individuals There are studies that demonstrate that this actually starts in utero where the fetus can be exposed to the mother’s lipoproteins
Clinically we would say that this disease manifests during the 4th-6th decades of life That means it begins when someone is in their 30s, 40s or 50s
We typically see a full decade difference between men and women This is something where women have a distinct advantage That’s not true for other diseases; for Alzheimer’s disease women ar at a distinct disadvantage
This happens very early in life for some individuals
There are studies that demonstrate that this actually starts in utero where the fetus can be exposed to the mother’s lipoproteins
That means it begins when someone is in their 30s, 40s or 50s
This is something where women have a distinct advantage That’s not true for other diseases; for Alzheimer’s disease women ar at a distinct disadvantage
That’s not true for other diseases; for Alzheimer’s disease women ar at a distinct disadvantage

“ I think it’s safe to say that if you do an autopsy on most men who die from some other reason in their 30s, you will find evidence of significant atherosclerosis ”— Peter Attia

Case studies of atherosclerosis and figures showing real pathology [43:00]

These pictures are actual pathology slides from one of Peter’s favorite books, which Allan Sniderman gave him his first copy— the Atlas of Atherosclerosis Progression and Regression by Herbert Stary

Herbert Stary is a pathologist who has devoted his career to understanding atherosclerosis through the lens of autopsies
Below are a series of cross-sections Recall the earlier figures were viewing the artery cut the long way Most people think of cutting an artery in a cross-section
The lumen should be perfectly patent, meaning perfectly open (shown in figure 19)
Recall the earlier figures were viewing the artery cut the long way
Most people think of cutting an artery in a cross-section

Figure 19. The pro part of the left anterior descending artery from a 29-year old female homicide victim. [ source ]

Part of this artery is normal and part is in the early stages of atherosclerosis

Figure 19 was taken from the pro (or close part) of the left anterior descending artery This was taken from a 29 year old female homicide victim Wikipedia has a simple diagram of the anatomy of the left coronary artery
Normal is shown at the top and bottom of figure 19 The endothelium is a tiny cell layer that you can barely see on the closest side to the lumen Then you get into the intima, the adventitia, and the muscular wall at the very outer side
This was taken from a 29 year old female homicide victim
Wikipedia has a simple diagram of the anatomy of the left coronary artery
The endothelium is a tiny cell layer that you can barely see on the closest side to the lumen
Then you get into the intima, the adventitia, and the muscular wall at the very outer side

We’re not going to get too much into the types of lesions because the nomenclature has changed since this book was written, but we’ll list how they were labeled for comparison

Figure 19 was referred to as type II lesion In the middle area, proximal LAD [left anterior descending branch of the coronary artery], foam cells are accumulating and they’ve led to intimal thickening The darker rim in the thickened part is behind the intima This is how we know these are foam cells in the intima that have lead to its thickening This woman would not have any symptoms even though this is in her LAD (a very important artery in the heart) The narrowing of the lumen is not clinically relevant This also would not show up on a calcium score (we’ll come back to this metric later)
In the middle area, proximal LAD [left anterior descending branch of the coronary artery], foam cells are accumulating and they’ve led to intimal thickening
The darker rim in the thickened part is behind the intima This is how we know these are foam cells in the intima that have lead to its thickening
This woman would not have any symptoms even though this is in her LAD (a very important artery in the heart)
The narrowing of the lumen is not clinically relevant
This also would not show up on a calcium score (we’ll come back to this metric later)
This is how we know these are foam cells in the intima that have lead to its thickening

Intimal thickening is an early sign of atherosclerosis

Figure 20 shows a more advanced lesion (type IV)

Figure 20. The proximal, middle left anterior descending artery of a 23-year old male homicide victim. [ source ]

This was a type IV lesion in the proximal, middle left anterior descending, artery of a 23-year old male victim of homicide

Why is this a more advanced lesion?

There is an enormous lipid core disrupting the musculoelastic layer above the media layer
This is now in a deeper part of the artery wall than the previous one
Notice where it says “fo”, there are foam cells and macrophages , but there’s no increase yet in the smooth muscle or the collagen fiber
This is still an early lesion
The luminal narrowing is not clinically significant
The patient would not experience any chest pain or any distress under any circumstance

Figure 21 shows another type IV lesion

Figure 21. The left main coronary artery from a 19-year old male suicide victim. [ source ]

This is the left main coronary artery, the most important artery in the body
In this case, the extracellular lipid and even the cholesterol in there has been crystallized
This is a particularly worrisome sign when you start to see this type of crystallization in the lipid core, because this is even more inflammatory This is probably more likely to elicit an immune response
This is in a 19-year old
This is probably more likely to elicit an immune response

Figure 22 shows a type V lesion

Figure 22. [ source ]

This is a type V lesion in the proximal (so the upper part of the left anterior descending) artery of a 38-year old male accident victim
This is a much more advanced lesion
The lipid core extends into the media
Parts of the media and the adventitia (that’s the back most layer) contain macrophages and lymphocytes [inflammatory cells]
There’s already fibrous tissue in the intima beyond what is normal That means the intimal layer is starting to thicken with smooth muscle
That means the intimal layer is starting to thicken with smooth muscle

If Peter had a crystal ball, and if this person didn’t die in a car accident— would they live to age 65?

Probably not
Still, at age 38 they would be completely asymptomatic
Their calcium score would be normal

Figure 23 shows a complete cross section of the artery; some is normal and some is not

Figure 23. Cross section of the proximal LAD from a 24-year old man who died suddenly. [ source ]

This is a cross section of the proximal, so the upper LAD, left anterior descending artery If you get a blockage here, you’re dead
This is from a 24-year old man who died suddenly with no clear explanation, even after autopsy (a rare occurrence) Based on the autopsy, it it doesn’t look like he died of a heart attack
This is a type IV lesion that was 1.5 cm long It starts about a centimeter before the bifurcation of the LAD in the circ This means it’s a very high lesion
In the middle position here, you can see the full atheroma, so you can see the full core of lipid
And at the upper and lower edge of the lesions was also something called the type III lesion
If you get a blockage here, you’re dead
Based on the autopsy, it it doesn’t look like he died of a heart attack
It starts about a centimeter before the bifurcation of the LAD in the circ This means it’s a very high lesion
This means it’s a very high lesion

Coronary artery lesions present in autopsies of different age groups [49:15]

Figure 24 is a graph from Stary’s book

The nomenclature is not that helpful because we don’t refer to them as type I’s, II’s, III’s, and IV’s anymore

The graph is still relevant because it shows the age prevalence of these types of lesions

Figure 24. Types of coronary artery lesions present in autopsies of different age groups. [ source ]

Nobody has preatheromas or advanced lesions up until age 11 These are types III, IV, and V
After age 11, the graph starts to steadily climb
By age 40, 70% of people have these types of lesion s (types III, IV, and V) He looked at nearly 700 autopsies per age group This is staggering
These are types III, IV, and V
He looked at nearly 700 autopsies per age group
This is staggering

“ If we do this today, it’s going to look a little bit better ”— Peter Attia

This was done 10-15 years ago in soldiers coming home from Afghanistan
Incidence of these things would shift a bit today due to 2 things 1 – Fewer people smoke today Smoking exacerbates this 2 – People generally have better control of lipids There is more use of lipid lowering medication today That probably plays less of a role in people under 40
1 – Fewer people smoke today Smoking exacerbates this
2 – People generally have better control of lipids There is more use of lipid lowering medication today That probably plays less of a role in people under 40
Smoking exacerbates this
There is more use of lipid lowering medication today
That probably plays less of a role in people under 40

The causal factors of ASCVD that determine prevention strategies [52:15]

When thinking about prevention, start with what causes this disease

Cholesterol causes this disease
Other things play a causal role Hypertension Smoking Metabolic health Metabolic health is perhaps the most important, subtle thing that is not appreciated here
Hypertension
Smoking
Metabolic health Metabolic health is perhaps the most important, subtle thing that is not appreciated here
Metabolic health is perhaps the most important, subtle thing that is not appreciated here

You want to manage lipids to prevent ASCVD

Typical cholesterol panels

The bare bones panel is going to be a total cholesterol, an LDL cholesterol, an HDL cholesterol, and a triglyceride (TG)

“ I’d rather know your eye color than your total cholesterol ”— Peter Attia

Total cholesterol includes all the lipoproteins in your bloodstream The total concentration of cholesterol contained in the : LDL + HDL + VLDL + Lp(a) There really aren’t any IDLs; they don’t stick around very long
The total concentration of cholesterol contained in the : LDL + HDL + VLDL + Lp(a)
There really aren’t any IDLs; they don’t stick around very long

Hypothetical total cholesterol = 250 mg/dL

LDL cholesterol is the cholesterol content within the LDL cholesterol particles
HDL cholesterol is the concentration cholesterol in the HDL particles
Triglycerides are the storage forms of fat that reside within those lipoproteins So that LDL and the VLDL (which we didn’t talk about here, because that’s typically not showing up in a standard lipid panel) will also include triglyceride Triglycerides can also be found in albumin, which is another binding protein
So that LDL and the VLDL (which we didn’t talk about here, because that’s typically not showing up in a standard lipid panel) will also include triglyceride
Triglycerides can also be found in albumin, which is another binding protein

Peter’s tip— make sure you’re getting an LDL that is direct, not indirect

Formulas are used to calculate LDL in low-bar labs
ut you want to use a lab that is doing a direct measure
The result will always say that it’s direct or indirect So just makes sure you’re getting a direct LDL
You should go one step further and measure VLDL cholesterol This will allow for a non-HDL cholesterol A non-HDL cholesterol is the sum of all the cholesterol minus the HDL That’s basically the LDL cholesterol + VLDL cholesterol Non-HDL cholesterol is always going to be more than LDL cholesterol
Understand that the cholesterol in each particle (LDL, HDL, etc) is all the same cholesterol
The amount of cholesterol within the HDL particle is a very crude metric that provides little indication of the functionality of the HDL
So just makes sure you’re getting a direct LDL
This will allow for a non-HDL cholesterol
A non-HDL cholesterol is the sum of all the cholesterol minus the HDL That’s basically the LDL cholesterol + VLDL cholesterol Non-HDL cholesterol is always going to be more than LDL cholesterol
That’s basically the LDL cholesterol + VLDL cholesterol
Non-HDL cholesterol is always going to be more than LDL cholesterol

HDLs are very important and they do really amazing things to help you reduce your risk of atherosclerosis. The problem is measuring how much cholesterol is in them doesn’t tell you if they’re doing their job well.

apoB

The podcast with Allan Sniderman went into great detail about apoB and why it’s important This is a great episode to flag for watching later Peter’s not going to attempt to do justice to explaining its importance
This is a great episode to flag for watching later
Peter’s not going to attempt to do justice to explaining its importance

Think back to figure 3, showing a cartoon of the endothelial layer in the artery and the LDL flowing in the bloodstream. What determines the probability that one of those LDLs kicks off this whole miserable thing by entering the subendothelial space, getting retained, getting oxidized, etc?

It turns out to be stochastic The particle concentration [LDL] is what determines this probability The more particles you have, the more likely it is that particles will go and enter the subendothelial space
This is unambiguously clear from not just the Mendelian randomization, but also genetic evaluations When you look at people who genetically have no other difference from the rest of us, except that they are unable to make much cholesterol, or they genetically clear LDL particles out of circulation in their liver at a dramatic rate, such that their LDL concentration is very low, they simply don’t get heart disease There are people walking around who genetically have LDL cholesterol levels of 10 to 20 milligrams per deciliter— this is the level of an infant These people don’t get heart disease
The particle concentration [LDL] is what determines this probability
The more particles you have, the more likely it is that particles will go and enter the subendothelial space
When you look at people who genetically have no other difference from the rest of us, except that they are unable to make much cholesterol, or they genetically clear LDL particles out of circulation in their liver at a dramatic rate, such that their LDL concentration is very low, they simply don’t get heart disease
There are people walking around who genetically have LDL cholesterol levels of 10 to 20 milligrams per deciliter— this is the level of an infant These people don’t get heart disease
These people don’t get heart disease

“ That goes through the causal relationship of LDL to this ”— Peter Attia

It’s not the amount of cholesterol within the LDL that’s a great predictor of the risk
It’s the number of LDL particles (and atherogenic particles in general) that’s a good predictor of risk

Nothing captures that better than apoB

Even though LDL is the dominant player here, there are also VLDL remnants These are VLDL particles that stick around way too long
There are Lp(a) particles In Peter’s practice, apoB is the most important metric they look at to predict risk (though not the only marker)
These are VLDL particles that stick around way too long
In Peter’s practice, apoB is the most important metric they look at to predict risk (though not the only marker)

Labs to identify biomarkers of ASCVD ]59:00]

The full lipid panel — he always wants to see the non-HDL cholesterol
Lp(a) (measured at least once) If it’s elevated, he might look again, depending on certain interventions
apoB
APOE (genotype) apoB and APOE are largely unrelated for the purpose of this
If it’s elevated, he might look again, depending on certain interventions
apoB and APOE are largely unrelated for the purpose of this

These measures tell about the risk but not how much atherosclerosis is currently present

There are not great biomarkers for assessing how much atherosclerosis is present
The biomarkers for predicting risk are useful so we can lower risk by reducing them
Additional measurements factor into how risk is managed: Homocysteine Uric acid Thyroid function Iron Ferritin
Realize these are biomarkers; he still looks at metabolic health with biomarkers and non-biomarkers He’s aggressive in monitoring blood pressure Even slight elevations of blood pressure are important A lot of this can be treated through changes in behavior
Homocysteine
Uric acid
Thyroid function
Iron
Ferritin
He’s aggressive in monitoring blood pressure Even slight elevations of blood pressure are important A lot of this can be treated through changes in behavior
Even slight elevations of blood pressure are important
A lot of this can be treated through changes in behavior

Diagnostic tests to determine the level of arterial damage present—CAC, CTA, CIMT, and more [1:00:30]

What diagnostics can capture the level of damage currently present in the arteries?

The pathology slides discussed earlier show different levels of damage
Biomarkers won’t differentiate this

The 2 most important things we can look at are:

1 – Coronary artery calcium (CAC) score
2 – A CT angiogram (CTA)

Calcium score (CAC)

This is done by doing a very quick CT scan of the heart without any intravenous contrast
It looks at the amount of calcification in the coronary arteries This is very late in the disease process
Once you have calcium formation around coronary arteries you’re at the 2nd to last stage of atherosclerosis It’s a late stage of healing Calcium formation is a very advanced finding of disease but it doesn’t tell you much about what’s happening at the point of calcification
Just yesterday, Peter got a patient’s calcium score back and it was not a very high number, but it wasn’t 0 That’s already a big red flag It was at one part of their heart, but that doesn’t really tell much The fact that they have a score of, say 15 at one part of their left anterior descending really means nothing about what’s happening there But that becomes a real global alarm given that person’s age (early 40s) Further, if they have a calcified point right there, they undoubtedly have atherosclerosis elsewhere
This is very late in the disease process
It’s a late stage of healing
Calcium formation is a very advanced finding of disease but it doesn’t tell you much about what’s happening at the point of calcification
That’s already a big red flag
It was at one part of their heart, but that doesn’t really tell much
The fact that they have a score of, say 15 at one part of their left anterior descending really means nothing about what’s happening there
But that becomes a real global alarm given that person’s age (early 40s)
Further, if they have a calcified point right there, they undoubtedly have atherosclerosis elsewhere

The CT angiogram (CTA) is a much better test

But it comes at a higher cost and it comes with more radiation At really good places, it should be in the ballpark of 2 millisieverts of radiation That’s a very small dose of radiation, about 4% of your annual allotted radiation, according to the NRC
A CT scan of the heart (this one is with contrast) captures the calcification They typically run a dry scan first to look for calcium But then once the contrast is in, you can see with great illumination the arteries This gives a better sense of the luminal narrowing and the presence of soft plaque
At really good places, it should be in the ballpark of 2 millisieverts of radiation That’s a very small dose of radiation, about 4% of your annual allotted radiation, according to the NRC
That’s a very small dose of radiation, about 4% of your annual allotted radiation, according to the NRC
They typically run a dry scan first to look for calcium
But then once the contrast is in, you can see with great illumination the arteries
This gives a better sense of the luminal narrowing and the presence of soft plaque

Really, the CAC and the CTA are a very important thing that we use also in risk prediction, especially if the patient is themselves on the fence about preventative measures

How can CIMT (carotid intima media thickness) be helpful in understanding ASCVD?

CIMT is an ultrasound that’s done of the carotid arteries in the neck
Peter finds this to be a completely unhelpful test for a couple of reasons: 1 – It is so user dependent in terms of the operator The operator needs amazing technical skill to get a really good look at those carotid arteries 2 – If you will want to see a change in this, you pretty much have to have the same person doing it again and again.
This might be that this is helpful if you have major, major carotid stenosis Evenstill, Peter would still prefer to to a CTA in this situation
There are no guidelines that are based on a CIMT
People look to this test because it has no radiation, but the CAC has virtually no radiation
1 – It is so user dependent in terms of the operator
The operator needs amazing technical skill to get a really good look at those carotid arteries
2 – If you will want to see a change in this, you pretty much have to have the same person doing it again and again.
Evenstill, Peter would still prefer to to a CTA in this situation

“ I don’t see an advantage of CIMT over CAC ”— Peter Attia

Interpreting results of CIMT can be confusing
A negative CIMT doesn’t tell much; it’s easy to miss things here
Obviously if there is a lot disease in the carotid artery, the CIMT will show it

Peter prefers a CAC over a CIMT

Calcium scores: keys to understanding and interpreting a CAC score and/or CTA results [1:05:15]

For many patients, Peter doesn’t bother getting a CAC score If it’s not going to add any benefit to what they’re already doing for risk prevention Depending on family history
The CAC score is not something that you follow serially over time
It’s used a couple times to establish risk
If it’s not going to add any benefit to what they’re already doing for risk prevention
Depending on family history

More about what the CAC score means

Figure 25. Odds ratio (adjusted) of coronary heart disease for different CAC scores. Credit: American Journal of Cardiology 2006

Figure 25 is a table taken from the Family Heart Study, published in 2006
It looked at CAC scores on a little over 3,000 subjects between 2002, 2004
About 400 of these people were clinically diagnosed with CHD
These patients were all asymptomatic at the initial exam The initial exam took place 7-9 years earlier
Basically what you’re looking at is calcium score progression to coronary events in people who were asymptomatic at the time of outset
Look at the odds ratio (adjusted) row in the middle The easiest way to think about the odds ratio is by comparing all these columns to the 1st column A 1.2 in the 2nd solemn is a 20% greater risk relative to the 1st column An odds ratio of 2.0 is 100% greater risk (a doubling of risk) compared to the 1st column
What you’re looking at in figure 25 is the number of people who had events versus those who didn’t have events based on their calcium score There is a clear relationship between the increase in the calcium score (CAC) and the likelihood of a cardiac event
A CAC of 0 is used as the unit case
A CAC of 1-49 is generally considered low and is a 1.2 increase in risk over 8 years
A CAC of 50-99 nearly doubles the risk
A CAC of 100-199 has an odds ratio of up to 3.8
By the time the calcium score is 2,000 , the odds ratio is 55.7, significantly higher
When Peter had his calcium score measured at age 35 it was 6 6 is a very low number when the scores go up to 2,000 At age 36 this put him at about the 75th percentile of the population
The initial exam took place 7-9 years earlier
The easiest way to think about the odds ratio is by comparing all these columns to the 1st column A 1.2 in the 2nd solemn is a 20% greater risk relative to the 1st column An odds ratio of 2.0 is 100% greater risk (a doubling of risk) compared to the 1st column
A 1.2 in the 2nd solemn is a 20% greater risk relative to the 1st column
An odds ratio of 2.0 is 100% greater risk (a doubling of risk) compared to the 1st column
There is a clear relationship between the increase in the calcium score (CAC) and the likelihood of a cardiac event
6 is a very low number when the scores go up to 2,000
At age 36 this put him at about the 75th percentile of the population

“ That was, of course, for me, the huge wake up call to learn everything I could about this disease and mitigate that risk .”— Peter Attia

The CAC was really valuable for him because his lipids weren’t that high
Much of that risk was mediated through things that are not easy to measure, such as family history
At the other end of the spectrum, he has patients that are in their 60s who have “ ragingly high lipids ”, and they’re really hell bent about not taking lipid lowering medication For them a calcium score becomes a very helpful way to assess whether or not lipid lowering medication should be discussed in greater detail
If a patient who’s 70 has a calcium score of zero, even in the presence of high lipids, you might be more willing to acknowledge that this is a person for whom, despite having very high lipids, may have something that’s offering protection Peter would have this person get a CT angiogram because of all the reasons that calcification alone is not sufficient He’s want to look at the lumen for evidence of soft plaque He’s seen people in their 70s who have really normal CTA despite abnormal lipids, but they are the exception
For them a calcium score becomes a very helpful way to assess whether or not lipid lowering medication should be discussed in greater detail
Peter would have this person get a CT angiogram because of all the reasons that calcification alone is not sufficient
He’s want to look at the lumen for evidence of soft plaque
He’s seen people in their 70s who have really normal CTA despite abnormal lipids, but they are the exception

Thinking about CAC scores, when is calcium even starting to show up?

This is a late stage event
Thinking back to the pathology reviewed earlier from autopsies, none of these patients had calcification Yet you could see they all had a pretty significant burden of disease
Figure 26 (below) is from a more recent paper; this shows cross-sections of coronary arteries The nomenclature uses more current language, but we’re not going to get into that
Yet you could see they all had a pretty significant burden of disease
The nomenclature uses more current language, but we’re not going to get into that

Figure 26. Credit: Journal of the American College of Cardiology 2010

The first one (A) is still abnormal
Normal would be just a beautiful gray rim
In (A) there is intimal thickening all the way around PIT stands for pathological intimal thickening
The one at the most right (E) is where you start to see calcification occur (E) shows a fibrocalcific lesion that can be picked up with a calcium score
PIT stands for pathological intimal thickening
(E) shows a fibrocalcific lesion that can be picked up with a calcium score

The point here is how many people can still be missed

You can still be in A, B, C, D, and have a normal calcium score
Only in E is your calcium score abnormal
But a CT angiogram can pick up A, B, C, D
Every patient and doctor have to make the decision— when is it worth the additional cost and the slight increase in the amount of radiation to have a much better test than one that can only detect E?

There’s nothing that’s black and white. It’s not every patient should do this, everyone should do this. It’s dependent on all these different factors, and together, which I think shows the importance of why diving into this and understanding .

The calcium score is nuanced

There’s now evidence to suggest that even the calcium score by itself is not sufficient in terms of just understanding calcium versus no calcium
It turns out that the density of the calcium also matters
When you’re looking at a CT scan, the bigger the Hounsfield unit, the denser the material that the x-ray is shining through The unit CT density is something called a Hounsfield unit At very low Hounsfield units (for example,looking at the lungs, because you have the least tissue there) the x-ray can zip right through it The highest Houndsfield units is when you’re stopping at bone
If you then look at just the differences in the Hounsfield units at the calcification of the coronary artery, that tells you something The denser the calcium, the lower the risk This is a little counterintuitive to people, which is calcification by itself is not a bad thing It’s actually a good thing; it’s stabilizing the plaque It’s just that it’s a harbinger of what’s going on
The unit CT density is something called a Hounsfield unit
At very low Hounsfield units (for example,looking at the lungs, because you have the least tissue there) the x-ray can zip right through it
The highest Houndsfield units is when you’re stopping at bone
The denser the calcium, the lower the risk This is a little counterintuitive to people, which is calcification by itself is not a bad thing It’s actually a good thing; it’s stabilizing the plaque It’s just that it’s a harbinger of what’s going on
This is a little counterintuitive to people, which is calcification by itself is not a bad thing
It’s actually a good thing; it’s stabilizing the plaque
It’s just that it’s a harbinger of what’s going on

When Peter tries to describe it to patients, he compared it to bars over the window in a house

If you walk into a neighborhood and see bars all over the window, you can at least conclude that no one’s entering that window
But what does it tell you about the neighborhood you’re in?

Is there a risk from cholesterol levels being too low? [1:13:00]

Is there a risk from having cholesterol be too low?

The good news is, no
When you look again at the laboratory report and look at lipid concentrations, you’re looking at what the amount of cholesterol contained within the lipoproteins circulating within the plasma

Total cholesterol

Consider the biggest reduction in total cholesterol you could have

Let’s say you lowered your total cholesterol from 200 mg/dL to 100 mg/dL
Along the way, you lowered your LDL cholesterol from 130 mg/dL to 40 mg/dL These are realistic numbers for what that type of dramatic reduction would do Question— how much have you lowered total body cholesterol in the process?
These are realistic numbers for what that type of dramatic reduction would do
Question— how much have you lowered total body cholesterol in the process?
Consider figure 27 from a study done by Mark Hellerstein This looks at the total body stores and pools of cholesterol
This looks at the total body stores and pools of cholesterol

Figure 27. Credit: Current Opinion in Lipidology 2014

The middle column shows the concentration of cholesterol
To make the math easy, the right-hand column is adjusted for a 70 kg person and shows the total grams of cholesterol
This shows the total amount of cholesterol in 4 places where it would largely concentrate 1 – Liver 2 – Red blood cells have lots of cholesterol in them 3 – Lipoproteins , this is what we’ve been talking about 4 – All the peripheral tissues of the body , obviously where the dominant amount is
Lipoproteins account for less than 10% of total body cholesterol
1 – Liver
2 – Red blood cells have lots of cholesterol in them
3 – Lipoproteins , this is what we’ve been talking about
4 – All the peripheral tissues of the body , obviously where the dominant amount is

Even if you shrink the cholesterol in lipoproteins by 50%, you’re only reducing total body cholesterol by 4.5%

This would be an enormous reduction, although it’s one that he will routinely does in patients
The vast majority of cholesterol still resides in peripheral tissue, and that’s where it’s being turned into hormones

Key takeaways regarding prevention [1:15:45]

Overall takeaway: Think about prevention decades in advance

ASCVD is very common
The good news is, this disease takes a really long time to occur It’s not going to happen overnight The flip side of that is it takes a while to prevent it as well
It’s not going to happen overnight
The flip side of that is it takes a while to prevent it as well

It’s a disease that is like moving towards an iceberg at three knots from hundreds of miles away. Just like a slow moving ship towards an iceberg, you can’t wait until you’re looking at the iceberg to do anything about it.

“ You have to be very forward looking in your assessment of risk. ”— Peter Attia

Studies look at the effects of drugs (like a statin) over the course of 2 years The key here is 2 years ; this speaks to the nature of this disease Often you may not see impressive results in this period of time
The FOURIER and ODYSSEY trials were 5 year studies published in 2014 or 2015 These looked at 2 PCSK9 inhibitors and showed very impressive results This is especially impressive given that one of them was done in patients who were already on maximum statin dose
The key here is 2 years ; this speaks to the nature of this disease
Often you may not see impressive results in this period of time
These looked at 2 PCSK9 inhibitors and showed very impressive results
This is especially impressive given that one of them was done in patients who were already on maximum statin dose

“You want to be thinking about this through the lens of not 5 years worth of prevention, but 10, 20, 30 years of prevention.” —Peter Attia

Takeaway: The importance of understanding apoB

The other big takeaway is the importance of understanding apoB and why apoB concentration is such an important metric It’s not the only metric, but when you want to think about lipids, you want to think about apoB
ApoB captures the risk much better than LDLC, and even non HDLC This is discussed at length in the podcast with Allan Sniderman
We will have an upcoming podcast on Lp(a) to go deep into that topic Lp(a) is very relevant for about 10% of the population
Everybody should know their Lp(a) and if it’s elevated, this opens a whole new Pandora’s box of things to think about prevention-wise
It’s not the only metric, but when you want to think about lipids, you want to think about apoB
This is discussed at length in the podcast with Allan Sniderman
Lp(a) is very relevant for about 10% of the population

Takeaway related to calcium scores :

Calcium scores are really good tests
The CTA is a much better test than the coronary artery calcium (CAC) score ; You just have to decide if the additional cost and radiation are worth it
Peter likes the CTA more than the CAC because it’s harder to get fooled
The CAC is a great way to stratify risk, but you’re going to miss a lot of pieces of pathology if they haven’t reached the level of calcification yet
You just have to decide if the additional cost and radiation are worth it

Selected Links / Related Material

Source of figure 1 : Risk of Premature Cardiovascular Disease vs the Number of Premature Cardiovascular Events | JAMA Cardiology (AD Sniderman et al 2016) | [6:45]

Episode of The Drive with Alan Sniderman : #185 – Allan Sniderman, M.D.: Cardiovascular disease and why we should change the way we assess risk | Host Peter Attia, The Peter Attia Drive Podcast (November 29, 2021) | [22:00]

Episode of The Drive with Rick Johnson, discusses the impact of uric acid on blood vessel endothelium : #194 – How fructose drives metabolic disease | Rick Johnson, M.D. | Host Peter Attia, The Peter Attia Drive Podcast (November 29, 2021) | [22:45]

Deep discussion of atherosclerosis as a systemic condition of the arterial system : The Myth of the “Vulnerable Plaque” | Journal of the American College of Cardiology (A Arbab-Zadeh and V Fuster 2015) | [37:15]

Source of pathology slides, the Herbert Stary Atlas : Atlas of Atherosclerosis Progression and Regression (Encyclopedia of Visual Medicine Series) by Herbert C. Stary (2003) | [43:30]

Source for figure 25 : Association of coronary artery calcified plaque with clinical coronary heart disease in the National Heart, Lung, and Blood Institute’s Family Heart Study | American Journal of Cardiology (PN Hopkins et al. 2006) | [1:05:45]

Source for figure 26 : The Dynamic Nature of Coronary Artery Lesion Morphology Assessed by Serial Virtual Histology Intravascular Ultrasound Tissue Characterization | Journal of the American College of Cardiology (T Kubo et al 2010) | [1:10:00]

Source for figure 27 : Reverse cholesterol transport fluxes | Current Opinion in Lipidology (M Hellerstein and S Turner 2014) | [1:14:15]

Read more on the website about preventing cardiovascular disease : Cardiovascular Disease | peterattiamd.com (2022)

Read more on the website about what Mendelian randomization studies reveal about LDL-C : LDL-C & systolic blood pressure and lifetime risk of cardiovascular disease | peterattiamd.com (November 10, 2019)

People Mentioned

Tom Dayspring [13:15, 50:15]
Alan Sniderman [22:00, 43:30, 56:30, 1:18:15]
Richard (Rick) Johnson [22:45]
Valentin Fuster [37:15]
Herbert Stary [43:30, 49:15]
Mark Hellerstein [1:14:30]

Transcript

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