Good Calories, Bad Calories

This was the research Gofman first reported in Science in 1950. He described how his ultracentrifuge “fractionated” lipoproteins into different classes depending on their density, and he noted that one particular class of lipoproteins, which would later be identified as LDL,^*42 is more numerous in patients with atherosclerosis than in healthy subjects, in men than in women, in older individuals than in younger, and particularly conspicuous in diabetics, all of which suggested a possible role in heart disease. What these low- density lipoproteins did not do, Gofman reported, was to reflect consistently the amount of cholesterol in the blood, even though they carry cholesterol within them. Sometimes total cholesterol levels would be low in his subjects, he noted, and yet the concentration of these low-density lipoproteins would be abnormally high. Sometimes total cholesterol would be high while the cholesterol contained in the low-density lipoproteins was low. “At a particular cholesterol level one person may show 25 percent of the total serum cholesterol in the form of [low-density lipoproteins], whereas another person may show essentially none in this form,” Gofman wrote.

After Science published Gofman’s article, and after aggressive lobbying on Gofman’s part, the National Advisory Heart Council agreed to fund a test of his hypothesis that lipoproteins are the important factor in heart disease and that cholesterol itself is not. The test would be carried out by four research groups—led by Gofman at Berkeley, Irving Page at the Cleveland Clinic, Fred Stare and Paul Dudley White at Harvard, and Max Lauffer of the University of Pittsburgh—that collectively identified five thousand men who were free of heart disease. When heart disease eventually appeared, they would determine whether total cholesterol or Gofman’s lipoproteins was the more accurate predictor.

While the three Eastern laboratories took three years to learn how to use an ultracentifruge for fractionating lipoproteins, Gofman proceeded with his own research, refined his understanding of how these lipoproteins predicted heart disease, and he then insisted that the analysis techniques be updated accordingly. The other investigators, however, were having considerable trouble duplicating Gofman’s original analysis, and so they refused to accept any further modifications.

In 1956, the four groups published a report in the American Heart Association journal Circulation, with a minority opinion written by Gofman and his Berkeley colleagues and a majority opinion authored by everyone else. As the majority saw it, based on the state of Gofman’s research in 1952, cholesterol was indeed a questionable predictor of heart disease risk, but the measurements of lipoproteins added little predictive power. “The lipoprotein measurements are so complex,” the majority report declared, “that it cannot be reasonably expected that they could be done reliably in hospital laboratories.” Gofman’s minority opinion, based on the state of his research in 1955, was that LDL and VLDL, the very low-density lipoproteins, were good predictors of heart disease, but that the single best predictor of risk was an atherogenic index, which took into account these two lipoprotein classes measured individually and added them together. The greater the atherogenic index, the greater the risk of atherosclerosis and heart disease.

Gofman would later be vindicated, but the majority opinion prevailed at the time: studying lipoproteins held no value in the clinical management of heart disease. Gofman and his Berkeley collaborators continued the research alone through 1963, when Gofman left to establish a biomedical-research division at the Lawrence Livermore National Laboratory and spent the rest of his career working on the health effects of radiation.

Lost entirely in the contretemps were the dietary implications of Gofman’s research. “While it is true that, for certain individuals, the amount of dietary fat is an important factor,” Gofman explained, “it turns out that there are other more significant factors that need to be considered. Human metabolism is so regulated that factors other than the actual dietary intake of one of these constituents may determine the amount of that constituent that will circulate in the bloodstream. Indeed, important observations have been made which indicate that certain substances in the diet that are not fatty at all may still have the effect of increasing the concentration of the fat-bearing lipoprotein substances in the blood.”

Though Gofman’s studies had demonstrated that the amount of LDL in the blood can indeed be elevated by the consumption of saturated fats, it was carbohydrates, he reported, that elevated VLDL— containing some cholesterol and most of the triglycerides in the blood—and only by restricting carbohydrates could VLDL be lowered.

This fact was absolutely critical to the dietary prevention of heart disease, Gofman said. If a physician put a patient with high cholesterol on a low-fat diet, that might lower the patient’s LDL, but it would raise VLDL. If LDL was abnormally elevated, then this low-fat diet might help, but what Gofman called the “carbohydrate factor” in these low-fat diets might raise VLDL so much that the diet would do more harm than good. Indeed, in Gofman’s experience, when LDL decreased, VLDL tended to rise disproportionately. And if VLDL was abnormally elevated to begin with, then prescribing a low-fat, high-carbohydrate diet would certainly increase the patient’s risk of heart disease.

This was why Gofman described the measurement of total cholesterol as a “false and highly dangerous guide” to the effect of diet on heart disease. Total-cholesterol measurements tell us nothing about the status of VLDL and LDL. Prescribing low-fat diets indiscriminately to anyone whose cholesterol appears to be elevated, or bombarding us with “generalizations such as ‘we all eat too much fat,’ or ‘we all eat too much animal fat,’” would increase heart-disease risk for a large proportion of the population. “Neglect of [the carbohydrate] factor can lead to rather serious consequences,” wrote Gofman in 1958, “first, in the failure to correct the diet in some individuals who are very sensitive to the carbohydrate action; and second, by allowing certain individuals sensitive to the carbohydrate action to take too much carbohydrate as a replacement for some of their animal fats.”

By 1955, Pete Ahrens at Rockefeller University had come to this same conclusion, although Ahrens was specifically studying triglycerides, rather than the VLDL particles that carry the triglycerides. Ahrens was considered by many investigators to be the single best scientist in the field of lipid metabolism. He had observed how the triglycerides of some patients shoot up on low-fat diets and fall on high-fat diets. This led Ahrens to describe a phenomenon that he called carbohydrate-induced lipemia (an excessive concentration of fat in the blood). When he gave lectures, Ahrens would show photos of two test tubes of blood serum obtained from the same patient—one when the patient was eating a high-carbohydrate diet and one on a high-fat diet. One test tube would be milky white, indicating the lipemia. The other would be absolutely clear. The surprising thing, Ahrens would explain, was “that the lipemic plasma was obtained during the high-carbohydrate period, and the clear plasma during the high-fat regimen.” (Joslin had reported the same phenomenon in diabetics thirty years earlier. “The percent of fat” in the blood, he wrote, “rises with the severity of the disease…and is especially related to the quantity of carbohydrate, which is being oxidized, rather than with the fat administered.”)

Over the course of a decade, Ahrens had seen only two patients whose blood serum became cloudy with triglycerides after eating high-fat meals. He had thirteen in whom carbohydrates caused the lipemia. Six of those thirteen had such high triglycerides that they had originally been referred to Ahrens from physicians who had misdiagnosed them as having a genetic form of high cholesterol. Since the VLDL particles that transport triglycerides, as Gofman had noted, also carry cholesterol and so contribute to the total cholesterol in the circulation, an elevated triglyceride level can elevate total cholesterol along with it. Ahrens believed that the fat- induced lipemia was a rare genetic disorder but the carbohydrate-induced lipemia was probably “an exaggerated form of the normal biochemical process which occurs in all people on high-carbohydrate diets.” In both cases, the fat in the blood would clear up when the subjects went on a low-calorie diet. To Ahrens, this explained why the carbohydrate-induced increase in triglycerides was absent in Asian populations living primarily on rice. As long as they were eating relatively low-calorie diets compared with their level of physical activity, which was inevitably the case in such impoverished populations, the combination would counteract the triglyceride-raising effect of the carbohydrates.