Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part II:the early evidence linking hypercholesterolemia to coronary disease in humans

Daniel Steinberg

doi:10.1194/jlr.r400012-jlr200

Abstract

The first in this series of historical reviews dealt with the pioneering animal model work of Anitschkow, implicating blood cholesterol in the pathogenesis of atherosclerosis, and the pivotally important work of Gofman, providing evidence that lipoprotein-bound cholesterol was a major factor in the human disease. This second installment reviews the early lines of evidence linking hypercholesterolemia in humans to the progression of atherosclerosis and the risk of coronary heart disease. The argument is made that by 1970, the evidence was already strong enough to justify intervention to lower blood cholesterol levels if all the available lines of evidence had been taken into account. Yet, it would be almost two decades before lowering blood cholesterol levels became a national public health goal. Some of the reasons the "cholesterol controversy" continued in the face of powerful evidence supporting intervention are discussed.

Highlights

The first in this series of historical reviews dealt with the pioneering animal model work of Anitschkow, implicating blood cholesterol in the pathogenesis of atherosclerosis, and the pivotally important work of Gofman, providing evidence that lipoprotein-bound cholesterol was a major factor in the human disease
The first was the groundbreaking studies of Anitschkow and others, showing that inducing hypercholesterolemia in rabbits was sufficient to produce arterial lesions closely resembling those in the human disease
The second focus in the preceding review was on the work of Gofman and coworkers [7], which revealed the complexity of the plasma lipoproteins in humans and demonstrated, albeit with only relatively small numbers of subjects, good correlations between elevated concentrations of plasma lipoproteins and relative risk of clinical coronary heart disease (CHD)

Summary

THE CLINICAL AND GENETIC EVIDENCE

The first hints that CHD might be linked to cholesterol or other lipids came from scattered anecdotal case reports of children with xanthomas, large deposits of lipids just beneath the skin or attached to tendon sheaths on the backs of the hands or at the ankles. He recognized that these cases were quite distinct, and he designated a separate category for what he called “primary essential xanthomatosis of the hypercholesterolemic type.” In his comprehensive 1938 review of xanthomatous diseases [27], he rejected the idea that the cholesterol esters in the lesions were deposited there from the blood. Like the Swiss endocrinologist in our parable above, American physicians could not handle the idea that a significant part of our population might be “abnormal.” And yet we know that that was exactly the case—20% or more of Americans with blood cholesterol levels that were once considered “normal” are working their way toward a heart attack. Returning to the early postwar decades, there were almost no data to turn to in order to decide whether risk was a continuous function of blood cholesterol level or whether there was a “threshold” level

THE EPIDEMIOLOGIC EVIDENCE

The Japanese migration studies

The Framingham Heart Study

DIETARY INTERVENTION TRIALS

Findings

THE WARS CONTINUE