Heart disease and cholesterol: a new hope

Heart disease and cholesterol- a new hope

Heart disease: the car, the driver & the crash

Complex disease processes are best explained with analogies. Heart disease is no exception. To explain two competing theories of heart disease I’ll use an analogy consisting of a driver, a car and a crash.

The anatomy of the heart and its more extended vascular system is the car. Some people have better genetics giving them stronger, more disease-proof hearts, just like some cars are more crash resistant.

The driver of the car determines in large part what will happen to the car. Minimizing your exposure to the factors “driving” the process of heart disease makes you less likely to die of it. Will you die of old age (slowly drive your sputtering car to the scrap yard many years after buying it)? Or will you die of a heart attack young (smashing the car against a wall shortly after leaving the dealership)?

Figuring out exactly what happened to a crashed car can help determine how it was being driven and what caused the crash. Understanding the slow-motion car crash that is heart disease can help us figure out how the disease process is driven and by what. In our analogy, the car hitting a wall head on and crumpling its engine is like the arteries getting slowly narrower, harder and gunked up with cholesterol til the heart gives out.

The car

Heart disease is also called CAD (coronary artery disease) and CVD (cardiovascular disease). Strokes and heart attacks are a subset of CVD. At this point it doesn’t really matter what we call the problems affecting the network of veins, arteries and capillaries making up our vascular system because there’s so much overlap between them. It extends out from our heart all the way up to top of your head and down to your toes. The vascular system is also known as the circulatory system. Ugh. If we could just settle on one name for one thing!

I prefer to to talk about “CVD” because it’s a broader term summing up the system in question: heart + network of blood vessels throughout your body. Got it. Car = the cardiovascular system.

Cars nowadays are involved in lots of crashes. CVD currently kills about 1 in 3 adults in the US [1]. It wasn’t always like that. The first signs of CVD in humans were found right around when Grok left his cave to till the wheat field [2]. So what has changed in the mean time that is now killing so many of us? It’s most likely the much greater exposure to drivers of arteriosclerosis that are part of modern lifestyles.

The driver

The driver in our analogy is all the factors actively damaging our cardiovascular systems, going on to trigger our body’s response mechanisms serving to repair the damage. Driver = causes of CVD. This post isn’t a deep discussion parsing through various drivers of CVD but they’re worth mentioning to get a more complete picture. The National Institute of Health (NIH) lists 5 major ones. I’ve taken the liberty to amend them

Subbotin CVD

They get the first one right. Don’t smoke, bravo!

They get the second wrong. The NIH makes 2 mistakes that aren’t obvious from the list alone. First, “certain fats” undoubtedly refers to saturated fats. Second, the more fat and in particular saturated fats and cholesterol you eat, the more these show up in your blood, right? [3,4]. No, that’s wrong [5].

Saying it like the NIH are, it’s easy to think that the more fat and cholesterol in the blood, the more of it will accumulate in arteries, right? Nope, that’s wrong too [6,7]. We shouldn’t forget that one study found that close to three quarters of patients were admitted to a hospital for a heart attack despite their cholesterol levels putting them in the low risk category [8]!

They get the third one right. Chronically high blood pressure damages the cardiovascular system.

For the fourth one, close but no cigar! They omit what’s arguably the most important factor, “high amounts of insulin” in the blood as a driver of CVD [9,10].

They’re on the right track with the fifth one but eventually drop the ball, confusing inflammation for a cause of damage when it is in effect a response to damage and necessary for repair. It’s akin to confusing the firefighter with the arsonist.

Lastly, they don’t include the consumption of high-omega6 vegetable oils as a driver of CVD [11,12]. Nina Teicholz and Dr.Eric Thorn give a nice overview of this in their Medscape article [13].

The crash

Crash = the process of cardiovascular disease. It’s also called arteriosclerosis. This is when coronary arteries get gunked up with cholesterol mostly, undergo stenosis (narrowing) and become less flexible due to fibrous calcified plaque building up. It’s a slow-motion car crash happening over decades. It’s illustrated in this graph from the American Heart Association [14].

Mainstream hypothesis | Car crash 1

The mainstream or current consensus hypothesis of how life-threatening cardiovascular disease happens goes something like this.

The hollow part of the coronary artery, where blood flows, is called the lumen. The blood flowing through the lumen carries with it spherical particles called lipoproteins. Lipoproteins carry cholesterol amongst other things.

The main protein organizing the structure of lipoprotein particles is called apolipoprotein B100, or apoB for short. Since there’s one apoB per lipoprotein, the number of apoBs tells you how many cholesterol carrying particles you have. This doesn’t include HDL lipoproteins because they use apoA, not apoB.

According to this theory, the more apoB-using lipoproteins in your blood, the more likely one is to penetrate the artery. Moreover, LDL lipoproteins are the smallest particles amongst those using the apoB protein and this is part of why LDL and other apoB particles are considered atherogenic. It’s analogous to a net or sieve letting through smaller stones rather than larger ones. Stones that get through are atherogenic.

The more of these lipoproteins you have in your blood, especially the smaller ones, the more cholesterol-rich gunk builds up in your arteries. This is sometimes referred to as the gradient hypothesis. Peter Attia, a medical doctor who has contributed brilliantly to the conversation on heart disease, sums it up saying “when LDL particle concentration is elevated, the lipoprotein penetrates into the subendothelial space” [15].

In order to better understand the problems with the gradient hypothesis, we need to examine what an adult’s normal coronary artery looks like [16]. Here, the part of the artery in contact with blood flowing through the lumen is labeled ‘endothelium’. It sits atop the tunica intima that’s thought to be 1 – 2 cells thick in a healthy state.

artery structure

According to this understanding of anatomy of coronary arteries, the tunica media layer should always be thicker than the tunica intima layer in healthy adult coronary arteries. However, that the tunica intima should stay 1 – 2 cells thick throughout the life of a healthy person is based on faulty anatomical observations. This anatomical description is unequivocally false.

artery structure intima

In fact, in this model it’s assumed that the thickening of the tunica intima can only be a pathological process. I’ll deconstruct this further when discussing a promising alternative theory to this one pushed by Dr.Vladimir Subbotin.

The picture below shows a healthy coronary artery and an arteriosclerotic one according to a 1 – 2 cell thick model of the tunica intima [17].

In this theory of arteriosclerosis, the apolipoproteins invasion goes from internal to external. More specifically, it starts from the lumen, progressing through deeper and deeper layers of the coronary artery, in the following order: endothelium, tunica intima, internal elastic membrane, tunica media, external elastic membrane and tunica externa.

I’ll challenge this theory by offering up Subbotin’s better one. I’m confident it’s at least less wrong.

Alternative hypothesis | Car crash 2

This alternative hypothesis needs a name but we’ll refer to it as Subbotin’s theory of arteriosclerosis for now. It hinges on 2 important differences.

First, it’s normal for the tunica intima to be thicker than the tunica media in healthy adult coronary arteries. Second, the pattern of lipid deposition observed in coronary arteries requires an alternative path of apolipoprotein invasion.

Tunica intima is thicker than the tunica media

In this theory, a normal, healthy adult tunica intima is thicker than the tunica media. In fact, infants younger than a year old infant have a 1 to 2 cell thick tunica intima, a 15 year old’s is 10 to 15 cells thick and an adult between the ages of 25 and 30 has a tunica intima of 25 to 30 cells thick [18].

It appears that a normal adult tunica intima thickens with age to accommodate the greater mechanical constraints of the adult cardiovascular system. The mainstream model assumes a thickened tunica intima must be pathological. This is an important anatomical difference with consequences for how we understand the progression of the disease (the slow-motion car crash in our analogy).

Alternative path of apolipoprotein invasion

In Subbotin’s theory of arteriosclerosis, apolipoproteins start invading the coronary artery from the tunica externa (external) towards the lumen (internal). More specifically, it starts with an invasion of the network of blood vessels (vasa vasorum) found in the tunica adventitia that slowly progresses through layers of the coronary artery, going into the tunica externa all the way to the tunica intima and endothelial cells.

Here’s what this looks like [19]


Notice the small network of blood vessels on the outside (external part) of the coronary artery spreading inwards towards the lumen. These blood vessels carry the cholesterol rich apolipoprotein particles, represented here by little yellow circles (visible in the the zoom box in the lower picture).

As you would expect from an external to internal invasion of apolipoproteins, their lipid and cholesterol rich cargoes accumulate further away from the lumen and as time goes on, more and more accumulate closer to the lumen. This is in fact what we see in Dr. Nakashima’s beautiful high-resolution images of coronary arteries at different stages of arteriosclerosis [20]


If, like in the mainstream theory, apolipoproteins invade from the lumen, you’d expect cholesterol to build up in the layers closer to it first (tunica intima). And only as arteriosclerosis progresses more and more would cholesterol make its way deeper into the coronary artery (external), meaning layers further away from the lumen.  

But that’s not what we see. The theory doesn’t fit the observations made by Dr.Nakashima. What we should do is change our theory to fit these observations, which is exactly what Subbotin’s theory does.


  • ‘high cholesterol’ or high LDL cholesterol is not a useful predictor of arteriosclerosis
  • The major drivers of arteriosclerosis identified so far are high blood sugar, high insulin levels, high blood pressure, smoking and consumption of high omega-6 vegetable oils
  • The mainstream theory of arteriosclerosis is based on faulty anatomical observations, it assumes apolipoproteins invade coronary arteries from the lumen and thus cannot explain the pattern of lipid deposition. Lastly, it assumes tunica intima thickening is always pathological instead of adaptive to the demands of the adult cardiovascular system
  • Subbotin’s alternative theory of arteriosclerosis can better explain the pattern of lipid deposition because it proposes that apolipoproteins invade the coronary artery from the tunica externa rather than the lumen. The theory correctly recognizes that an adult tunica intima should be thicker than the tunica media. With this understanding, it can then distinguish between a tunica intima that is thicker to adapt to the demands of an adult cardiovascular system and one that thickens due to the arteriosclerotic process

6 comments On Heart disease and cholesterol: a new hope

  • Dr Attia is emphatic regarding the role of LDL (C, P) in clinically significant vascular disease and the power of modifying life style factors in manageing risk, but also the consumption of pharmaceuticals. He is completely wedded to your CAR 1. Perhaps we are generally advising some appropriate strategies but still for the” wrong” reasons (since mechanisms and individual responses are so hopelessly complex). Does it actually matter?

    I am amused that he sits with patients and reads from his pathology and molecular biology bibles as a way to convince folks to comply with advice. I supposes for his mostly very motivated crew….preaching to the choir.

    • Hi Hap,

      I agree with what you say about being ‘right for the wrong reasons’. I’d venture it’s likely that our best advice often works for reasons different than we give. It does matter because having the wrong reasons limits our scope of improvement and may even mislead us in using what we know from some treatments to invent others. Nevertheless, just because we may get mechanisms wrong doesn’t mean we should eschew our good (empirical) results.

      You seem to be describing how he deals with his patients – do you have any experience with him or know people who have?

      Thanks for your comment Hap

  • I wonder about insulin’s role in Subbotin’s hypothesis since it has pleiotropic effects on angiogenesis

  • Hi Justin,

    Interesting reference.

    Yeah it’s hard to figure out its exact role in coronary arteriosclerosis. As your reference points out, in T2D high insulin is associated with hypovascularization & reduced wound healing. Yet in cancer it directly and indirectly promotes angiogenesis.

    So what about its role in CVD? I posit it increases the volume of tissues occupying the various layers making up the artery. These, and especially the latter, increase hypoxic tissue area which gets the body to respond by increasing vascularization (angiogenesis) to reduce the area of hypoxic tissue. So, in this way, I believe insulin indirectly promotes angiogenesis in heart disease.

    Thanks for your comment Justing!

    • That’s good to hear; I was thinking along the same lines. Now all we need is an experiment to show it!

    • Thinking about it more, I believe a plausible hypothesis would be that hyperinsulinemia/insulin resistance causes increased endothelial (and cancer) growth via the MAPK pathway and decreased nitric oxide (with possibly decreased oxygenation) via the PI3K pathway. This would also explain delayed wound healing because 1. an increase in basal angiogenic factors would cause the body to be less responsive when a real need arises and 2. decreased oxygenation to the wound area. All this may be compounded by dysfunctional adipocyte signaling or possibly other mechanisms. Decreased FOXO activity may also play a role as FOXO activity is associated with longevity.

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