The evidence initially cited in support of the hypothesis came almost exclusively from animal research—particularly in rabbits. In 1913, the Russian pathologist Nikolaj Anitschkow reported that he could induce atherosclerotic-type lesions in rabbits by feeding them olive oil and cholesterol. Rabbits, though, are herbivores and would never consume such high-cholesterol diets naturally. And though the rabbits did develop cholesterol-filled lesions in their arteries, they developed them in their tendons and connective tissues, too, suggesting that theirs was a kind of storage disease; they had no way to metabolize the cholesterol they were force-fed. “The condition produced in the animal was referred to, often contemptuously, as the ‘cholesterol disease of rabbits,’” wrote the Harvard clinician Timothy Leary in 1935.

The rabbit research spawned countless experiments in which researchers tried to induce lesions and heart attacks in other animals. Stamler, for instance, took credit for first inducing atherosclerotic-type lesions in chickens, although whether chickens are any better than rabbits as a model of human disease is debatable. Humanlike atherosclerotic lesions could be induced in pigeons, for instance, fed on corn and corn oil, and atherosclerotic lesions were observed occurring naturally in wild sea lions and seals, in pigs, cats, dogs, sheep, cattle, horses, reptiles, and rats, and even in baboons on diets that were almost exclusively vegetarian. None of these studies did much to implicate either animal fat or cholesterol.

What kept the cholesterol hypothesis particularly viable through the prewar years was that any physician could measure cholesterol levels in human subjects. Correctly interpreting the measurements was more difficult. A host of phenomena will influence cholesterol levels, some of which will also influence our risk of heart disease: exercise, for instance, lowers total cholesterol. Weight gain appears to raise it; weight loss, to lower it. Cholesterol levels will fluctuate seasonally and change with body position. Stress will raise cholesterol. Male and female hormones will affect cholesterol levels, as will diuretics, sedatives, tranquilizers, and alcohol. For these reasons alone, our cholesterol levels can change by 20 to 30 percent over the course of weeks (as Eisenhower’s did in the last summer of his presidency).

Despite myriad attempts, researchers were unable to establish that patients with atherosclerosis had significantly more cholesterol in their bloodstream than those who didn’t. “Some works claim a significant elevation in blood cholesterol level for a majority of patients with atherosclerosis,” the medical physicist John Gofman wrote in Science in 1950, “whereas others debate this finding vigorously. Certainly a tremendous number of people who suffer from the consequences of atherosclerosis show blood cholesterols in the accepted normal range.”

The condition of having very high cholesterol—say, above 300 mg/dl—is known as hypercholesterolemia. If the cholesterol hypothesis is right, then most hypercholesterolemics should get atherosclerosis and die of heart attacks. But that doesn’t seem to be the case. In the genetic disorder familial hypercholesterolemia, cholesterol is over 300 mg/dl for those who inherit one copy of the defective gene, and as high as 1,500 mg/dl for those who inherit two. One out of every two men and one out of every three women with this condition are likely to have a heart attack by age sixty, an observation that is often evoked as a cornerstone of the cholesterol hypothesis. But certain thyroid and kidney disorders will also cause hypercholesterolemia; autopsy examinations of individuals with these maladies have often revealed severe atherosclerosis, but these individuals rarely die of heart attacks.