“The urgency of finding means of prevention is sharpest for men in middle age for it is in that group that the social cost of CHD is greatest…Starting with men aged 40 through 59, the follow-up would show CHD causing close to 40% of all deaths in five years. It is understandable, then, that most work on the epidemiology of CHD begins with men of those ages. Ancel Keys, The Seven Countries Study (1970) (ref 1 , p. I-1).”

Introduction

The first part of the diet–heart hypothesis, that serum cholesterol was related to coronary heart disease (CHD), originated from the work of Russian pathologists in the early 20th century. Having observed fatty deposits in arteries during postmortems, a number of researchers sought to understand if dietary cholesterol determined serum cholesterol.2–9 The summary of findings from the original animal studies was that: rabbits (herbivores) fed animal foods developed fatty deposits/changes in the aortas; rats (omnivores) fed animal foods produced no observable changes in the aortas; and rabbits fed cholesterol in plant food showed no arterial damage.

In the 1950s, Keys undertook several experiments with human subjects and concluded “that the cholesterol content, per se, of all natural diets has no significant effect on either the serum cholesterol level or the development of atherosclerosis in man” (ref. 10, p. 182).

The logic that only animal foods contain cholesterol and thus, if animal foods consumed to administer dietary cholesterol had no impact on serum cholesterol then animal foods per se had no impact on serum cholesterol was overlooked. Attention turned to dietary fat in food when non-animal foods would have been more logical to examine.

The second part of the diet–heart hypothesis, that dietary fat and serum cholesterol were related, followed observational studies of men in Minnesota, Naples, Slough and Madrid. Keys et al11 concluded that the total fat content of the diet (as a proportion of calories) exerted a powerful influence on the serum cholesterol level in man. Age appeared to be a confounder, with cholesterol rising to the age of 50–55 in Minnesotan and Slough men and rich men in Madrid. Neopolitan men and poor men in Madrid demonstrated stable and falling cholesterol levels, respectively, between the ages of 40 and 50, rising before these ages.

The third part of the diet–heart hypothesis, that dietary fat and CHD were related, was first presented with the graph of deaths from heart disease and calories from total fat in men aged 55–59, for six countries, from the Mount Sinai presentation of 1953.12 The response of Yerushalmy and Hilleboe13 demonstrated that data were available for 22 countries.

Keys et al10 concluded that no other variable, besides the fat calories in the diet, showed anything like such a consistent relationship to the mortality rate from CHD.

The first statement of the diet–heart hypothesis, with the three component parts, appears to have been made in a 1955 publication, which explored the relationship between dietary fat, serum cholesterol and CHD in different ethnic groups in Cape Town.14 This paper confirmed that total fat intake and animal fat intake were the subjects of examination. Saturated fat was not mentioned.

This was the context for the start of the Seven Countries Study in 1956–1958. The Seven Countries Study concluded that there was no relationship with total fat and CHD, but that there was a strong correlation between saturated fat intake and CHD in cross country comparison.1

In ideal research circumstances, epidemiological evidence would have established clear and consistent associations and then well designed randomised controlled trials (RCTs) would have followed epidemiological findings and set out to test associations found. This did not happen with the development of the diet–heart hypothesis. Possibly the sense of urgency took over. The epidemiology and RCTs were running in parallel from the 1950s onwards.

The focus on men, and men who had already had a heart attack in the case of the RCTs, was understandable in the context of the Keys' quotation opening this paper. This focus, however, lacked generalisability for the population as a whole.