The Origin of the Lipid Hypothesis — And Proposal of a New Term

In my last post (The Proper Use of the Term “Lipid Hypothesis”), I traced the origin of the term “lipid hypothesis” to Edward Ahrens in 1976, who defined it as the hypothesis that reductions in blood cholesterol levels will lead to reductions in heart disease risk.  This can be seen as a testable prediction of the underlying hypothesis that high concentrations of cholesterol in the blood cause heart disease.

Ahrens popularized the phrase and published what was apparently the first full-length paper devoted to defining it, but was not the first to use the phrase.  I included a footnote in the last post with a reference to Daniel Steinberg using it in print in 1974 with the exact same meaning.  There may be earlier references.

These authors used the term to refer to a hypothesis quite distinct from the diet-heart hypothesis, or the “diet-heart question,” terms that had first been used in the early 1960s and defined more clearly in the late 1960s under the supervision of a panel chaired by Ahrens.

While these events represent the origin of the term “lipid hypothesis,” they do not represent the origin of the hypothesis itself.  After all, while the lipid hypothesis does not in any way depend on the diet-heart hypothesis, the diet-heart hypothesis is directly dependent on the lipid hypothesis because it proposes that dietary fat, or dietary saturated fat, causes heart disease precisely by raising the concentration of cholesterol in the blood.  If the diet-heart hypothesis existed in the 1960s, certainly the lipid hypothesis also did.

The actual lipid hypothesis itself pre-dates the diet-heart hypothesis by decades and traces to Anitschkov's cholesterol-fed rabbit.  I have discussed this model in detail in my article, “High Cholesterol and Heart Disease — Myth or Truth?”

Anitschkov and his partner Chalatov never intended to investigate cholesterol and were following up on earlier work suggesting that dietary protein accelerated aging.  They were investigating atherosclerosis because it was seen as a sign of aging.

They found something quite different, and Anitschkov abandoned the idea of a dietary model of atherosclerosis in favor of a metabolic model.  Anitchkov was very clear that his work suggested nothing about dietary cholesterol in humans.

In a 1932 review,* cited in my Myth or Truth article, Anitschkov wrote the following (I will use bold for emphasis but all of the italics are his):

[I]n human atherosclerosis the conditions are different. It is quite certain that such large quantities of cholesterin are not ingested with the ordinary food. In human patients we have probably to deal with a primary disturbance of the cholesterin metabolism, which may lead to atherosclerosis even if the hypercholesterinemia is less pronounced, provided only that it is of long duration and associated with other injurious factors. . . . [O]n the basis of the experimental results we are certainly justified in stating that atherosclerosis belongs to the “metabolic diseases,” and that cholesterin is the “materia peccans.” [the “ill-making substance”]  It is not possible to deny that some other aspects of the metabolism can be disturbed at the same time, but in this respect hardly anything is known.

Anitschkov rejected the myopic view that cholesterol is “the cause” of atherosclerosis, as if any one molecule could be the single cause of a complex disease.  Nevertheless, he considered it essential to the disease.  A pre-requisite, but not the only factor.

It would be entirely wrong if, on the basis of these conclusions, we were to describe cholesterin or rather hypercholesterinemia as “the cause” of atherosclerosis.  But that cholesterin plays an important part in this process, as far as its etiology is concerned, has now been definitely established as a fact by these experiments. . . . In brief, atherosclerosis never develops without cholesterin. 

Anitschkov was very decisive in arguing that atherosclerosis is a multi-factorial disease:

But, to say it again, it would be wrong if, on the basis of these experimental results, we were to regard this factor as of exclusive etiologic significance.  On the contrary, all pertinent observations recorded in these experiments point to the probability that several factors contribute to the genesis of atherosclerosis  — factors both of a general and of a local nature.

 Anitschkov reviewed experimental evidence that the following factors also contribute to atherosclerosis:

• High blood pressure

• Local arterial injury

• Inflammation

• Other dietary factors (in the rabbit, protein)

He reviewed evidence that the following factors protect against athrosclerosis:

• Sex hormones

• Thyroid hormone

• Iodine

 And he considered it likely that the following factors may also play a role:

• Infection

• Disturbances in the nervous system

He concluded thus:

If we now survey all the experimental results in their entirety, we find that quite a number of different factors are involved in the etiology of atherosclerosis. . . . The views here set forth concerning the etiology of atherosclerosis constitute what I have called the “combination theory”of its origin.

The “lipid hypothesis,” then, from the beginning, never claimed exclusivity for cholesterol, and never denied the role of inflammation, hormones, infection, and other dietary and metabolic factors.  Nevertheless, it did give primacy to elevated levels of blood cholesterol.

Evaluating the lipid hypothesis is somewhat difficult, not only because misuse of terminology and conflation with the diet-heart hypothesis is so widespread (indeed, conflating these two hypotheses was exactly what led to the mass media's condemnation of fatty animal products in the 1980s, which will be the subject of the next post).  It is difficult because theories change over time as they attempt to accomodate new evidence.

Someone hell-bent on destroying the lipid hypothesis might accuse its proponents of creating a “moving target,” but the reality is that when a “beautiful hypothesis” confronts an “ugly fact,” its two legitimate choices are to change or die.Hardly any mainstream scientists would accuse evolutionary theory of creating “moving targets” because it has undergone a great deal of revision and expansion since Darwin.

I have described in my Myth or Truth article, and in my last Wise Traditions lecture, “Heart Disease and Molecular Degeneration: The New Paradigm,” what I would consider overwhelming evidence that the degeneration of lipids in the blood is essential to the initiation of atherosclerosis and plays a less prominent role in its progression.  I will provide further evidence of this several blog posts from now.

Is this a form of the lipid hypothesis?

There is nothing about the term “lipid hypothesis” that would suggest it is not.  After all, it is a hypothesis that involves lipids.

However, it is a hypothesis of a fundamentally different character from that of Anitschkov, Ahrens, and Steinberg, even though it heavily incorporates the experimental contributions of all of them.

Anitschkov considered one of the defining characteristics of his theory of atherosclerosis to be that it considered atherosclerosis infiltrative instead of degenerative.  He focused on the amount of cholesterol, as did Ahrens and Steinberg after him.

It may therefore be regarded as certain that in these experimental animals large quantities of the ingested cholesterin are absorbed, and that the accumulation of this substance in the tissues can only be interpreted as deposits of lipoids circulating in large quantities in the humors of the body.  The establishment of this fact is of importance, because it shows that atherosclerosis is not essentially of degenerative nature, but rather of an infiltrative character.

In fact, he even called his theory the “infiltration theory.”

Above all it has made it possible definitely to demonstrate that the initial stages of the process are in the nature of a lipoid infiltration or imbibition of the intima, and that the lipoids enter into the arterial wall from the lumen.  This has greatly strengthened the “infiltration theory” of atherosclerosis.

Anitschkov saw his “infiltration theory” as running in close partnership with his “combination theory.”

The views here set forth concerning the etiology of atherosclerosis constitute what I have called the “combination theory” of its origin.  This theory is closely related to the “infiltration theory” of the formal genesis of this disease, because both theories are in part based on the operation of identical factors as established mainly by recent experimental research.

I think that Anitschkov's belief that atherosclerosis was infiltrative rather than degenerative (that is, that any degeneration followed infiltration of the lipid driven by its high concentration in the blood) was the most reasonable theory at the time, given the evidence available to him.

However, our understanding of the molecular mechanisms of atherosclerosis has progressed dramatically since his time, and we have definitive evidence that it is degeneration of lipids rather than their high concentration that drives atherosclerosis.

Yet proponents of the “lipid hypothesis” have nevertheless subjugated this evidence to constitute a mechanism for a theory that remains fundamentally infiltrative in character, based fundamentally on the amount of lipid in the blood.

I think, then, that the term “lipid hypothesis” is insufficient.  Anitschkov, brilliant as he was, used much better terminology.  If only it involved the term lipid or cholesterol, it would have been perfect.

I propose, then, that my view — that degeneration of lipids plays an essential role in the initiation of atherosclerosis and a less prominent role in its progression — is a lipid hypothesis, but it is not THE lipid hypothesis.

I propose a new terminology to distinguish between these two related but fundamentally different hypotheses:

• The infiltrative lipid hypothesis is the hypothesis of Anitschkov, Ahrens, Steinberg, and the medical establishment, focused on the amount of cholesterol in the blood driving its infiltration into the arterial wall, and considering this infiltration to drive any subsequent degeneration.

• The degenerative lipid hypothesis is the hypothesis that considers the amount of cholesterol largely or perhaps entirely irrelevant, and considers the degeneration of lipids in the blood to drive their infiltration into the arterial wall, and this infiltration to actually be partly protective against worse forms of degeneration that would have occurred in its absence.

Lest we become myopic, we should fully retain Anitschkov's combination theory as a powerful and intimate partner of the degenerative lipid hypothesis.

* Anitschkow N. Experimental Arteriosclerosis in Animals. In: Cowdry EV. Arteriosclerosis: A Survey of the Problem. New York: Macmillan. 1933.