Good Calories, Bad Calories (33 page)

cholesterol and wil have an insignificant effect, if any, on the ratio of total cholesterol to HDL. Al of this suggests that eating a porterhouse steak in lieu of bread or potatoes would actual y reduce heart-disease risk, although virtual y no nutritional authority wil say so publicly. The same is true for lard and bacon.

“Everything should be made as simple as possible,” Albert Einstein once supposedly said, “but no simpler.” Our understanding of the nutritional causes of heart disease started with Keys’s original oversimplification that heart disease is caused by the effect of al dietary fat on total serum cholesterol. Total cholesterol gave way to HDL and LDL cholesterol and even triglycerides. Al fat gave way to animal and vegetable fat, which gave way to saturated, monounsaturated, and polyunsaturated fat, and then polyunsaturated fats branched into omega-three and omega-six polyunsaturated fats. By the mid-1980s, these new levels of complexity had stil not deterred the AHA and NIH from promoting carbohydrates as effectively the antidote to heart disease, and either al fats or just saturated fats as the dietary cause.

What would now become apparent was that LDL cholesterol is little more than an arbitrary concept that oversimplifies its own complex diversity. The fact that LDL and LDL cholesterol are not synonymous complicates the science. Just as Gofman had reported in 1950 that cholesterol itself was divided up among different lipoproteins, and those lipoproteins had different atherogenic properties and responded differently to diet, a lipid metabolism specialist named Ronald Krauss, using Gofman’s ultracentrifuge, began reporting in 1980 that low-density lipoproteins were in turn composed of different, distinct subclasses, each containing differing amounts of cholesterol, and each, once again, with different atherogenic properties and different behavior in response to the carbohydrates and fats in our diet. Although Krauss has long been considered one of the most thoughtful researchers in nutrition and heart disease—the American Heart Association has treated him as such—it’s worth noting in advance that his dietary research has been almost universal y ignored, precisely because of its ultimate implications for what constitutes a healthy diet and what does not.

LDL cholesterol is only a “marginal risk factor,” Tavia Gordon and his col eagues had observed in 1977. In other words, little difference can be observed between the average LDL cholesterol of those with and without heart disease. Only by comparing the LDL-cholesterol and heart-disease rates between nations (with al the attendant complications of such comparisons) can conspicuous differences be seen. In the analysis from Framingham, San Francisco, Albany, Honolulu, and Puerto Rico published by Gordon and his col aborators, the average LDL cholesterol of heart-disease sufferers was only a few percentage points higher than the average of those who remained healthy. “If you look in the literature and just look at the average coronary patients,” Krauss says, “their LDL-cholesterol levels are often barely discernibly elevated compared to patients who do not have coronary disease.”

In the late 1940s, Gofman and his col aborators began asking why the same level of LDL cholesterol wil cause heart disease in some people but not in others. Krauss and his col aborators began asking this question again, thirty years later.

Krauss himself is an idiosyncratic figure in this world. He has produced a dozen years of research suggesting that high-carbohydrate diets, for the great proportion of the population, are the nutritional cause of heart disease, and yet he has also chaired the nutrition committee of the American Heart Association and was the primary author of the 1996 and 2000 AHA nutrition guidelines. In the process, he eased the AHA away from its thirty-year-old position that the maximum fat content of a heart-healthy diet should be 30 percent of calories. Or, as Krauss remarked, he managed to put the “30-percent-fat recommendation in smal print.” Krauss trained as a physician in the late 1960s and then worked with Fredrickson and Levy at the NIH, where he discovered a protein known as hepatic lipase that regulates how the liver metabolizes lipoproteins. He then moved to Berkeley to practice internal medicine, and it was there, in 1976, that he began working with Gofman’s ultracentrifuge and with Alex Nichols and Frank Lindgren, both of whom had col aborated with Gofman in the 1950s.

When Krauss began his research at Berkeley, he had what he cal s “this conventional notion, which many people stil have, that LDL is just one thing, a single entity.” But that turned out not to be the case. Using data from the ultracentrifuge dating back to the early 1960s, Krauss discovered that LDL

actual y comes in distinct subspecies, al characterized by stil finer gradations in density and size. “It was blazingly obvious. Unignorable,” says Krauss.*49

Eventual y, Krauss identified seven discrete subclasses of LDL. He also noted that the smal est and densest of the low-density lipoproteins had two significant properties: it had a strong negative correlation with HDL, and it was the subspecies that was elevated in patients with heart disease.

In the early 1980s, Krauss published three papers on what he cal s the “remarkable heterogeneity of LDL,” al of which, he says, were met with indifference mixed with occasional hostility. Acceptance of Krauss’s research was also constrained by the fact that Gofman’s ultracentrifuge had been necessary to differentiate these LDL subclasses, which meant that this, too, was not the kind of measurement that could be ordered up easily by physicians. In his later publications, Krauss described a simpler, inexpensive measurement technique, but the research was stil perceived as an esoteric endeavor.

To understand the implications of this association between smal , dense LDL and heart disease, it helps to picture the configuration of the low-density lipoprotein itself. Imagine it as a bal oon. It has a single protein—known as apo B, for short—that serves as the structural foundation of the bal oon and holds it together. It has an outer membrane that is composed of cholesterol and fats of yet another type, cal ed phospholipids. And then, inside the bal oon, inflating it, are triglycerides and more cholesterol. The size of the LDL bal oon itself can vary, depending on the amount of triglycerides and cholesterol it contains. Thus, as Krauss reported, some people have mostly large, fluffy LDL, with a lot of cholesterol and triglycerides inflating the bal oon, and some people have mostly smal er, denser LDL particles, with less cholesterol and triglycerides.

In the 1970s, investigators had developed yet another way to quantify the concentration of these circulating lipoproteins, in this case by counting only the number of apo B proteins that provide the structural foundation to the LDL bal oon. Because there’s only one protein per LDL particle, and because VLDL is also composed of identical apo B proteins, this technique measured the number of LDL and VLDL particles in a blood sample, rather than the cholesterol or triglycerides they contained. As it turned out, the number of apo B proteins, and so the total number of LDL and VLDL particles combined, is also abnormal y elevated in heart-disease patients. This was first reported in 1980 by Peter Kwiterovich, a lipid-metabolism specialist from Johns Hopkins, together with Al an Sniderman, a cardiologist from McGil University. Kwiterovich and Sniderman then col aborated with Krauss on the last of his three papers on the heterogeneity of LDL. In 1983, they reported that the disproportionate elevation in the apo B protein in heart-disease patients was due to a disproportionate elevation in the amount of the smal est and densest of the low-density lipoproteins.

This explained what Krauss had set out to understand: why two people can have identical LDL-cholesterol levels and yet one develops atherosclerosis and coronary heart disease and the other doesn’t—why LDL cholesterol is only a marginal risk factor for heart disease. If we have low LDL cholesterol, but it’s packaged almost exclusively in smal , dense LDL particles—the smal er bal oons—that translates to a higher risk of heart disease. If we have high LDL cholesterol, but it’s packaged in a smal er number of large, fluffy LDL particles—the larger bal oons—then our heart-disease risk is significantly lower. Smal , dense LDL, simply because it is smal and dense, appears to be more atherogenic, more likely to cause atherosclerosis. Smal , dense LDL

can squeeze more easily through damaged areas of the artery wal to form incipient atherosclerotic plaques. Sniderman describes smal , dense LDL as the equivalent of “little bits of sand” that get in everywhere and stick more avidly. The relative dearth of cholesterol in these particles may also cause structural changes in the protein that make it easier for it to adhere to the artery wal to begin with. And because smal , dense LDL apparently remains in the bloodstream longer than larger and fluffier LDL, it has more time and greater opportunities to do its damage. Final y, it’s possible that LDL has to be oxidized—the biological equivalent, literal y, of rusting—before it can play a role in atherosclerosis, and the existing evidence suggests that smal , dense LDL oxidizes more easily than the larger, fluffier variety.

Through the 1980s, Krauss continued to refine this understanding of how LDL subspecies affect heart disease. He discovered that the appearance of LDL in the population fal s into two distinct patterns or traits, which he cal ed pattern A and pattern B. Pattern A is dominated by large, fluffy LDL and implies a low risk of heart disease; pattern B is the dangerous one, with predominantly smal , dense LDL. Pattern B is invariably accompanied by high triglycerides and low HDL. Pattern A is not. In 1988, Krauss and his col aborators reported in JAMA that heart-disease patients were three times more likely to have pattern B than pattern A. Krauss cal ed pattern B the atherogenic profile. Diabetics have the identical pattern.

The effect of diet on this atherogenic profile now became the pivotal issue. In the 1960s and most of the 1970s, the dietary goal was to lower total cholesterol. After the 1977 revelations about HDL, the best diet became the one that lowered LDL cholesterol and maybe raised HDL in the process. But if Krauss and his col aborators were right, a diet that lowers total cholesterol or LDL cholesterol can conceivably do so in a way that actual y increases the proportion of smal , dense LDL in the blood turning the healthy pattern A trait into the atherogenic pattern B. If we focus on LDL cholesterol alone, such a diet might appear to prevent heart disease. But if the size, density, and number of the LDL subspecies are indeed the important variables, the diet could in fact increase heart-disease risk.

Though pattern A and B traits appear to be strongly influenced by genetics, diet and other lifestyle factors play a critical role. In the late 1980s, Krauss began a series of clinical trials to explore the association between diet and the dangerous smal , dense LDL. The results of his seven trials have been consistent: the lower the fat in the diet and the higher the carbohydrates, the smal er and denser the LDL and the more likely the atherogenic pattern B

appears; that is, the more carbohydrates and the less fat, the greater the risk of heart disease.

On a diet that Krauss cal s the “average American diet,” with 35 percent of the calories from fat, one in three men wil have the atherogenic pattern B

profile. On a diet of 46 percent fat, this proportion drops: only one man in every five manifests the atherogenic profile. On a diet of only 10 percent fat, of the kind advocated by diet doctors Nathan Pritikin and Dean Ornish, two out of every three men wil have smal , dense LDL and, as a result, a predicted threefold higher risk of heart disease. The same pattern holds true in women and in children, but the percentages with smal , dense LDL are lower. Krauss and his col eagues even tested the effect of types of fat on these lipoproteins, and reported that, the more saturated fat in the diet, the larger and fluffier the LDL—a beneficial effect.*50

Though the concept of smal , dense LDL as a risk factor for heart disease has been accepted into the orthodox wisdom, as has Krauss’s atherogenic profile (although now renamed atherogenic dyslipidemia), his dietary research has had no perceptible influence on discussions of the dietary prevention of heart disease. The implications are so provocative that many investigators simply ignore them. Even those clinical investigators who firmly believe that smal , dense LDL is indeed the atherogenic form of LDL often refuse to comment on the dietary implications. “Wel , I would rather not get into that,” said the University of Washington epidemiologist Melissa Austin, who studies triglycerides and heart disease and has col aborated with Krauss on studies of the smal , dense LDL.

Goran Wal dius, a cardiologist at the Karolinska Institute in Stockholm, had the same response. Wal dius is the principal investigator of an enormous Swedish study to ascertain heart-disease risk factors. The 175,000 subjects include every patient who received a health checkup in the Stockholm area in 1985. Blood samples were taken at the time, and Wal dius and his col eagues have been fol owing the subjects ever since, to see which measures of cholesterol, triglycerides, or lipoproteins are most closely associated with heart disease. Far and away, the best predictor of risk, as Wal dius reported in 2001, was the concentration of apo B proteins, reflecting the dominance of smal , dense LDL particles. Half of the patients who died of heart attacks, he reported, had normal LDL-cholesterol levels but high apo B numbers. Apo B is a much better predictor of heart disease than LDL cholesterol, Wal dius said, because LDL cholesterol “doesn’t tel you anything about the quality of the LDL.” But when asked in an interview to comment on Krauss’s research and the subject of dietary interventions that might increase the size of LDL particles, Wal dius said, “I’l have to pass on that one.”

The notion that carbohydrates determine the ultimate atherogenicity of lipoproteins is surprisingly easy to explain by the current understanding of fat-and-cholesterol transport. This model also accounts neatly for the observed relationship between heart disease, triglycerides, and cholesterol, and so constitutes another level of the physiological mechanisms underlying the carbohydrate hypothesis. The details are relatively straightforward, but, not surprisingly, they represent a radical shift from the mechanisms envisioned by Keys and others, in which coronary artery disease is caused by the simple process of saturated fat raising total-cholesterol or LDL-cholesterol levels. This is another way in which the subspecialization of medical researchers works against progress. For most epidemiologists, cardiologists, internists, nutritionists, and dieticians, their knowledge of lipoprotein metabolism dates to their medical or graduate-school training. Short of reading the latest biochemistry textbooks or the specialized journals devoted to this research, they have few available avenues (and little reason, as they see it) for keeping up-to-date, and so the current understanding of these metabolic processes escapes them. The details of lipoprotein metabolism circa 2007 remain a mystery to the great proportion of clinicians and investigators involved in the prevention of heart disease.