Cholesterol Story Part 4

1 hour ago

7 min read

Cholesterol Lipid Hypothesis Part 4

Cholesterol Part IV: What Makes Atherosclerosis Progress?

Last week we walked through how atherosclerosis actually begins.

An ApoB-containing lipoprotein, most commonly an LDL particle, enters and becomes retained within the arterial wall. The immune system responds. Macrophages engulf modified lipoproteins and become foam cells, creating the beginnings of an atherosclerotic plaque.

That is the genesis of the lesion.

But it raises a much more interesting question.

Why does that lesion progress in some people while remaining relatively quiet in others?

There are millions of people walking around with elevated LDL particle numbers who will never suffer a heart attack. Conversely, cardiovascular events occur in people whose conventional LDL cholesterol does not appear particularly alarming.

That does not make LDL or ApoB unimportant. Far from it.

Higher lifetime exposure to ApoB-containing particles increases the probability of developing atherosclerosis. (Ference et. al. 2017) But probability is not destiny.

Something else helps determine what happens to that lesion once it is there.

And a major part of that story appears to be immune-metabolic inflammation.

This has become ground zero for my most recent deep dives into diseases in general.

Think back to the foam cell we created 2 weeks ago. The important question now is not simply whether that foam cell exists. The question is: Does the inflammatory response resolve or does the artery remain trapped in a state of chronic injury and attempted repair?

If the metabolic and inflammatory signals that created the unhealthy environment persist, macrophages continue to accumulate. Some become dysfunctional and die. Oxidized lipids, cellular debris, inflammatory cytokines, and cholesterol accumulate within the lesion. The immune system continues trying to clean up the mess while vascular cells simultaneously attempt to repair it.

This is no longer simply a cholesterol problem.

It has become a chronic immune-metabolic problem occurring inside an artery. (Libby et. al. 2002)

That distinction matters.

Consider the person with insulin resistance and visceral obesity. An enlarged fat cell is not simply a storage bag filled with calories. Adipose tissue is an active endocrine and immune organ.

As visceral fat cells enlarge and become dysfunctional, immune cells, particularly macrophages, accumulate within the tissue. The adipose tissue begins releasing altered patterns of immune signals called cytokines, adipokines, and free fatty acids.

The result is a biological environment characterized by increasing insulin resistance and chronic low-grade inflammation. (Glass et. al. 2012)

Meanwhile, insulin resistance changes what happens in the liver.

Triglyceride energy rich VLDL production increases. Lipoprotein cars remodel and increase in number. HDL cholesterol frequently falls, and the number and characteristics of ApoB-containing particles can become less favorable. This is the phenotypic pattern of ASCVD. (Ginsberg et. al. 2026)

Now we have two processes feeding one another: abnormal lipid trafficking and abnormal immune signaling. This is why obesity, insulin resistance, type 2 diabetes, fatty liver disease, hypertension, and cardiovascular disease cluster together so frequently.

They are interconnected manifestations of disturbed metabolism and inflammation.

I call this immune-metabolic inflammation.

Metabolism affects immunity.

Immunity affects metabolism.

And both affect what happens inside the artery.

For me, the key is that Inflammation predicts who has the event.

This brings us to a fascinating observation. If the number of LDL particles were sufficient to explain who eventually has a heart attack, inflammatory markers should add relatively little once we know someone's lipid burden.

But, alas, you guessed it, they do.

One of the best studied markers is high-sensitivity C-reactive protein, or hsCRP. More than two decades ago, Ridker and colleagues followed 27,939 initially healthy women and compared LDL cholesterol and hsCRP as predictors of a first cardiovascular event. Both predicted cardiovascular disease. But hsCRP produced a larger separation in future cardiovascular risk than LDL cholesterol. (Ridker et. al. 2002)

The investigators subsequently compared CRP with several lipid measurements, including ApoB100.

Again, ApoB, the volume of LDL type cholesterol, predicted cardiovascular risk. But CRP remained a powerful independent predictor and the risk gradient associated with CRP was greater than that associated with ApoB in this population. (Ridker et. al. 2005)

Then researchers followed the original Women's Health Study cohort for approximately 30 years. The results were remarkable. A single baseline measurement of hsCRP, LDL cholesterol, and Lp(a) independently predicted cardiovascular events decades later. Comparing women in the highest versus lowest quintiles, the adjusted hazard ratios for major cardiovascular events were:

hsCRP: 1.70

LDL cholesterol: 1.36

Lp(a): 1.33

And cardiovascular risk was greatest when these different biological pathways were considered together. (Ridker et. al. 2024)

That last point is critical.

This is not cholesterol versus inflammation.

It is cholesterol and inflammation.

We see the same phenomenon in people already being aggressively treated for their lipids.

A 2023 analysis combined more than 31,000 statin-treated patients participating in the PROMINENT, REDUCE-IT, and STRENGTH trials. Among these treated patients, residual inflammation measured by hsCRP was a stronger predictor of subsequent major cardiovascular events, cardiovascular mortality, and all-cause mortality than residual LDL cholesterol. (Ridker et. al. 2023)

Think about what that means.

You can successfully lower someone's LDL cholesterol and still leave behind substantial cardiovascular risk.

That remaining risk has become known as residual inflammatory risk. This is where I land in the cholesterol argument. We need to focus on the residual risk space to get the true ASCVD burden under control.

The American College of Cardiology's 2025 Scientific Statement on inflammation and cardiovascular disease now describes the relationship between chronic low-grade inflammation and ASCVD as compelling and clinically actionable. (Mensah et. al. 2025)

This is no longer an alternative theory of cardiovascular disease.

It is becoming part of mainstream cardiovascular medicine.

And it is about time.

What is the obvious next question? Is inflammation a marker or causative?

Perhaps hsCRP is simply telling us that something bad is happening without actually participating in the disease. That would make inflammation a useful marker, but not necessarily a driver.

The CANTOS trial helped answer that question. Researchers studied more than 10,000 people who had experienced a previous myocardial infarction and continued to have elevated hsCRP.

They treated patients with canakinumab, a drug targeting the inflammatory cytokine IL-1β.

The treatment lowered inflammatory signaling without lowering LDL cholesterol.

Cardiovascular events nevertheless decreased. (Ridker et. al. 2017)

That is enormously important.

If changing an inflammatory pathway reduces cardiovascular events without changing LDL cholesterol, inflammation cannot simply be an innocent bystander.

Subsequent trials using low-dose colchicine have provided additional evidence that reducing inflammatory signaling can lower cardiovascular events in selected patients with coronary disease. (Nidorf et. al. 2020)

We therefore have evidence from two directions:

1) Inflammation predicts cardiovascular events.

2) Treating inflammation can reduce cardiovascular events.

That makes the inflammatory biology very difficult to ignore.

Now, let us return to the person eating a highly processed Western diet while sleeping poorly, exercising little, accumulating visceral fat, developing insulin resistance, and perhaps smoking or living with chronic physiological stress.

The cardiovascular consequences are not produced through one pathway. There is no single villain. Instead, multiple biological pressures converge:

Insulin signaling deteriorates.

Visceral adipose tissue becomes inflammatory.

Hepatic lipid trafficking changes.

ApoB-containing particles increase in susceptible individuals.

Blood pressure may rise.

Oxidative stress increases.

Endothelial signaling becomes less healthy.

And inflammatory signaling remains chronically activated.

The artery containing that early lesion is living inside this biological environment every day.

That is the part of the cholesterol story that gets LOST when we think only about the concentration of LDL cholesterol in the bloodstream.

This is also where I would modify something I wrote several years ago.

I previously focused heavily on saturated fat and omega-6 vegetable oils as inflammatory drivers.

The science deserves more nuance.

Trans fats clearly increase cardiovascular risk and should be avoided. Replacing saturated fat with unsaturated fats, particularly polyunsaturated fats, can reduce LDL cholesterol and cardiovascular risk. And omega-6 fatty acids themselves should not simply be labeled "inflammatory"; human evidence does not support that broad conclusion. (Farvid et. al. 2014)

The larger concern is the dietary pattern. A diet dominated by ultra-processed foods, refined flour and sugar, excess calories, inadequate fiber and phytonutrients, and repeatedly heated or oxidized fats creates a very different metabolic environment from one based primarily on minimally processed whole foods.

The resulting insulin resistance, visceral adiposity, abnormal lipid trafficking, and inflammatory signaling are the issues that concern me most.

This pattern fits my over fueling hypothesis. The over consumption of carbon as food stuffs leads to mitochondrial damage through overwhelmed adaptive patterns like insulin resistance, mitochondrial leak and fatty acid storage. The overwhelmed adaptive mechanisms lead to excessive reactive oxygen metabolites that damage lipids, DNA and mitochondria in general. (Do et. al. 2025)

So let us put Parts III and IV together.

Last week we discussed how the lesion begins.

An ApoB-containing particle enters and becomes retained within the arterial wall.

That is critically important.

But today we have added the second half of the story:

What determines what happens next?

The number of atherogenic particles matters.

The length of time they circulate matters.

But so does the biological environment in which the developing plaque lives.

I think of it this way:

ApoB provides the opportunity for the lesion.

Immune-metabolic inflammation helps determine its trajectory.

That helps explain something that otherwise seems puzzling.

Two people can have similar LDL particle numbers yet experience very different cardiovascular outcomes.

One may remain free of clinical cardiovascular disease for decades.

The other may develop progressive plaque and eventually suffer a myocardial infarction.

Their LDL burden matters.

But it is not the only difference between them.

Their inflammatory biology, insulin sensitivity, visceral adiposity, blood pressure, smoking exposure, genetics, endothelial health, exercise, diet, sleep, and decades of cumulative exposure all help determine where they ultimately land.

The LDL particle may help start the lesion.

The biological environment helps determine whether that lesion becomes dangerous.

That is why cardiovascular prevention cannot end with lowering cholesterol.

Lower ApoB when appropriate.

But also ask why the inflammatory and metabolic environment exists in the first place.

Improve insulin sensitivity.

Reduce visceral adiposity.

Exercise.

Do not smoke.

Sleep.

Control blood pressure.

Eat real food.