Good Calories, Bad Calories

As in Japan, increases in fat consumption with coincident decreases in heart disease have occurred recently in Spain and Italy, which has prompted the observation that the French paradox—a nation that eats a high-fat diet and has little heart disease—has evolved into the French-Italian-Spanish paradox.^*24 Through the mid- 1990s, according to John Powles, an epidemiologist with the British Institute of Public Health, France and Italy both showed declines in death rates from stroke and heart disease that were greater than those in most European countries, while the decline in mortality in Spain lagged only slightly behind. And studies of Mediterranean immigrants to Australia suggest that the low heart-disease rates of these immigrants fall even lower in Australia, despite a considerable increase in their meat consumption.

In the late 1970s, the World Health Organization launched a research project known as MONICA, for “MONItoring CArdiovascular disease,” that was similar in concept to Keys’s Seven Countries Study but considerably larger. The study tracked heart disease and risk factors in thirty-eight populations in twenty-one countries—a total population of roughly six million people, which unlike previous studies included both men and women. Hugh Tunstall-Pedoe, the MONICA spokesman, has described the project as “far and away the biggest international collaborative study of cardiovascular disease ever carried out” and noted that, “whatever the results, nobody else has better data.” By the late 1990s, MONICA had recorded 150,000 heart attacks and analyzed 180,000 risk-factor records. Its conclusion: heart-disease mortality was declining worldwide, but that decline was independent of cholesterol levels, blood pressure, or even smoking habits.

The MONICA investigators suggested reasons why their study might not have confirmed Keys’s hypothesis, among them the possibility, as Tunstall-Pedoe noted, that with populations “the contribution of classical risk factors is swamped by that of other dietary, behavioral, environmental, or developmental factors.” He also discussed something that may have contributed initially to the widespread belief in Keys’s hypothesis: the tendency to publish or pay attention to only that evidence that confirms the existing beliefs about heart disease and risk factors. “If you do a study in your population and you show a perfect correlation between risk factors and heart disease, you rush off and publish it. If you don’t, unless you have great confidence in yourself, you worry that perhaps you didn’t measure something properly, or perhaps you’d better keep quiet, or perhaps there’s something you haven’t thought about. And by doing this, there is a risk of myths’ becoming self-perpetuating.” “There are people,” Tunstall-Pedoe said, “who want to believe that if we find anything less than 100-percent correlation between traditional risk factors and trends in heart disease, we are somehow traitors to the cause of public health, and what we say should be suppressed, and we should be ashamed of ourselves. Whereas we are asking a perfectly reasonable question, and we came up with results. That is what science is about.”

In the two decades since the NIH, the surgeon general, and the National Academy of Sciences first declared that all Americans should consume low-fat diets, the research has also failed to support the most critical aspect of this recommendation: that such diets will lead to a longer and healthier life. On the contrary, it has consistently indicated that these diets may cause more harm than good. In 1986, the year before the National Cholesterol Education Program recommended cholesterol-lowering for every American with cholesterol over 200 mg/dl, the University of Minnesota epidemiologist David Jacobs visited Japan, where he learned that Japanese physicians were advising patients to raise their cholesterol, because low cholesterol levels were linked to hemorrhagic stroke. At the time, Japanese men were dying from stroke almost as frequently as American men were succumbing to heart disease. Jacobs looked for this inverse relationship between stroke and cholesterol in the MRFIT data and found it there, too. And the relationship transcended stroke: men with very low cholesterol seemed prone to premature death; below 160 mg/dl, the lower the cholesterol, the shorter the life.

In April 1987, the Framingham investigators provided more reason to worry when they finally published an analysis of the relationship between cholesterol and all mortality. After thirty years of observation, there was a significant association between high cholesterol and premature death for men under fifty. But for those over fifty, both men and women, life expectancy showed no association with cholesterol. This suggested, in turn, that if low cholesterol did prevent heart disease, then it must raise the risk of dying from other causes.

This was compounded by what may have been the single most striking result in the history of the cholesterol controversy, although it passed without comment by the authorities: those Framingham residents whose cholesterol declined over the first fourteen years of observation were more likely to die prematurely than those whose cholesterol remained the same or increased. They died of cardiovascular disease more frequently as well. The Framingham investigators rejected the possibility that the drop in cholesterol itself was diet-related—the result of individuals’ following AHA recommendations and eating low-fat diets. Instead, they described it as a “spontaneous fall,” and insisted that it must be caused by other diseases that eventually led to death, but they offered no evidence to support that claim.

The association between low cholesterol and higher mortality prompted administrators at the National Heart, Lung, and Blood Institute once again to host a workshop and discuss it. Researchers from nineteen studies around the world met in Bethesda, Maryland, in 1990 to report their results. The data were completely consistent (see charts on following page): when investigators tracked all deaths, not just heart-disease deaths, it was clear that men with cholesterol levels above 240 mg/dl tended to die prematurely because of their increased risk of heart disease. Those whose cholesterol was below 160 mg/dl tended to die prematurely with an increased risk of cancer, respiratory and digestive diseases, and trauma. As for women, if anything, the higher their cholesterol, the longer they lived.^*25

The proponents of Keys’s hypothesis said the results could not be meaningful. The excess deaths at low cholesterol levels had to be due to pre-existing conditions; chronic illness leads to low cholesterol, they concluded, not vice versa, and then the individuals die from the illnesses, which confuses the mortality issue. This was the assumption the Framingham researchers had made. At the one end of the population distribution of cholesterol, low cholesterol is the effect and disease is the cause. At the other end of the distribution, high cholesterol is the cause and disease is the effect. This, of course, is a distinction based purely on assumptions rather than actual evidence, and one consistent with the universal recommendations to lower cholesterol by diet. When NIH Administrator Basil Rifkind offered this interpretation during my interview with him in 1999, he pointed to the report of the 1990 conference as the definitive document in support of it. But the report, which Rifkind co-authored, states unequivocally that this interpretation was not supported by the available evidence.

The relationship between blood cholesterol (horizontal axes) and all deaths (total mortality) or just heart disease deaths, as reported in a 1990 NIH conference.

In an alternate interpretation, both ends of the cholesterol distribution are treated identically. Whether high or low, either our cholesterol levels directly increase mortality or they’re a symptom of an underlying disorder that itself increases our risk of disease and death. In both cases, diet leads to disease, although whether it does so directly, via its effect on cholesterol, or through other mechanisms would still be an open question. In this interpretation, what a cholesterol-lowering diet does to cholesterol levels, and what that in turn does to arteries, may be only one component of the diet’s effect on health. So lowering cholesterol by diet might help prevent heart disease for some individuals, but it might also raise susceptibility to other conditions—such as stroke and cancer—or even cause them. This is what had always worried those investigators who were skeptical of Keys’s hypothesis. “Questions should be pursued about biological mechanisms that might help explain low [total cholesterol]: disease associations,” noted the report from the 1990 NHLBI workshop.