University of Minnesota

The Diet-Lipid-Heart Disease Hypothesis in Capsule

Habitual diet has been considered critical to health and to the cure and prevention of disease since antiquity and Hippocrates. The hypothesis of atherogenesis through diet fat to blood cholesterol level to atheroma and vascular diseases developed principally from experimental pathology. Russian pathologists, Ingatowski and Anitschkow, in the early 20th century produced human-type atheroma in rabbits and went on to address most of the issues of genesis and regression of atherosclerosis still pursued today.

Hypercholesterolemia was related clinically to atherosclerosis, independently of diet, in the late 19th and early 20th century, in familial blood lipid disorders, and thyroid and kidney diseases.

Informal epidemiology in Scandinavia during and after World War II indicated that deaths from heart attack and autopsy findings of atherosclerosis declined dramatically during the privations of war and rose promptly following the war. This suggested that diet, disappearance of fatty foods, and semi-starvation were involved, and that atherosclerosis, previously considered an inevitable consequence of aging, was mutable.

These findings led to major questions about diet, mainly dietary fat, and blood lipid levels, questions that were explored in the early 1950s among social classes of contrasting cultures by the informal epidemiological surveys of Ancel Keys, Paul D. White, and colleagues in Naples, Madrid, Cape Town, Japan, Hawaii, and Los Angeles, establishing differences consistent with the diet-lipid-heart hypothesis.

Formal epidemiology of coronary disease, in considerable part stimulated by the diet-heart question, began first in three centers, Minnesota, where Ancel Keys in 1947 hypothesized diet and lifestyle causes of epidemic heart attack in men, in Washington, D.C., where the U.S. government planned the Framingham Study to explore the biological and behavioral components of the epidemiological transition to cardiovascular and non-communicable disease deaths in the U.S., and in London, where Jeremy Morris largely rejected a primary role of diet but initiated prospective studies of occupation, diet, and other characteristics among UK civil servants.

John Gofman defined the physical and functional roles of blood lipoproteins, LDL, HDL, and VLDL and by 1950 had tied together, with a major synthesis, diet, blood, and pathological findings from laboratory, clinical, and epidemiological evidence. Much of his synthesis was rejected by the science establishment, but soon was confirmed and expanded by findings from all research disciplines.

Prospective epidemiological studies worldwide posed the major risk factor hypotheses beginning in the late 1940s, including diet and blood lipid factors, and by the mid-1950s the reports of these significant relationships devolved into a risk factor paradigm of the causes and prevention of CVD.

Consistently weak correlations within individuals between recall measures of diet fat consumption, blood cholesterol level, and CVD risk proved a major source of controversy and rejection of diet-heart concepts for some time. Strong ecologic correlations of diet fat and CVD rates among contrasting populations of the Seven Countries Study helped change judgments on this relationship. The powerful experimental evidence that blood lipid levels were predictably modifiable by specified changes in diet fatty acid and cholesterol composition solidified the evidence and set the stage for definitive “proof” by experiment.

The diet-lipid-atherosclerosis theory finally became widely accepted by the scientific community in the 1980s, but only after experimental evidence that lipid lowering —achieved in drug and surgical trials rather than in diet trials that had been judged infeasible— prevented heart attacks in humans.

The causal and preventive role of the diet-lipid-heart relation was tied together further by parallel elucidation of mechanisms in the laboratory: Brown and Goldstein’s work on the hepatic LDL receptors that regulate blood cholesterol levels, Steinberg’s findings that oxidized LDL was the major arterial pathogen, and laboratory and epidemiological evidence on the functional protective role of HDL. (Henry Blackburn)