In 1951, Keys had an epiphany while attending a conference in Rome on nutrition and disease, which focused exclusively, as Keys later recalled, on malnutrition. There he was told by a physiologist from Naples that heart disease was not a problem in his city. Keys found this comment remarkable, so he and his wife, Margaret, a medical technician whose specialty was fast becoming cholesterol measurements, visited Naples to see for themselves. They concluded that the general population was indeed heart-disease-free—but the rich were not. Margaret took blood-cholesterol readings on several hundred workers and found that they had relatively low cholesterol. They asked “a few questions about their diet,” Keys recalled, and concluded that these workers ate little meat and that this explained the low cholesterol. As for the rich, “I was taken to dine with members of the Rotary Club,” Keys wrote. “The pasta was loaded with meat sauce and everyone added heaps of parmesan cheese. Roast beef was the main course. Dessert was a choice of ice cream or pastry. I persuaded a few of the diners to come for examination, and Margaret found their cholesterol levels were much higher than in the workmen.” Keys found “a similar picture” when he visited Madrid. Rich people had more heart disease than poor people, and rich people ate more fat.

This convinced Keys that the crucial difference between those with heart disease and those without it was the fat in the diet. A few months later, he aired his hypothesis at a nutrition conference in Amsterdam—“fatty diet, raised serum cholesterol, atherosclerosis, myocardial infarction.” Almost no one in the audience, he said, took him seriously. By 1952, Keys was arguing that Americans should reduce their fat consumption by a third, though simultaneously acknowledging that his hypothesis was based more on speculation than on data: “Direct evidence on the effect of the diet on human arteriosclerosis is very little,” he wrote, “and likely to remain so for some time.”