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 small, dense LDL particles—the smaller balloons—that translates to a higher risk of heart disease. If we have high LDL cholesterol, but it’s packaged in a smaller number of large, fluffy LDL particles—the larger balloons—then our heart-disease risk is significantly lower. Small, dense LDL, simply because it is small and dense, appears to be more atherogenic, more likely to cause atherosclerosis. Small, dense LDL can squeeze more easily through damaged areas of the artery wall to form incipient atherosclerotic plaques. Sniderman describes small, 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 wall to begin with. And because small, dense LDL apparently remains in the bloodstream longer than larger and fluffier LDL, it has more time and greater opportunities to do its damage. Finally, it’s possible that LDL has to be oxidized—the biological equivalent, literally, of rusting—before it can play a role in atherosclerosis, and the existing evidence suggests that small, 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 falls into two distinct patterns or traits, which he called 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 small, dense LDL. Pattern B is invariably accompanied by high triglycerides and low HDL. Pattern A is not. In 1988, Krauss and his collaborators reported in JAMA that heart-disease patients were three times more likely to have pattern B than pattern A. Krauss called 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 collaborators were right, a diet that lowers total cholesterol or LDL cholesterol can conceivably do so in a way that actually increases the proportion of small, 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 small, dense LDL. The results of his seven trials have been consistent: the lower the fat in the diet and the higher the carbohydrates, the smaller 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 calls the “average American diet,” with 35 percent of the calories from fat, one in three men will 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 will have small, 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 small, dense LDL are lower. Krauss and his colleagues 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 small, 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 small, dense LDL is indeed the atherogenic form of LDL often refuse to comment on the dietary implications. “Well, I would rather not get into that,” said the University of Washington epidemiologist Melissa Austin, who studies triglycerides and heart disease and has collaborated with Krauss on studies of the small, dense LDL.
Goran Walldius, a cardiologist at the Karolinska Institute in Stockholm, had the same response. Walldius 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 Walldius and his colleagues have been following 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 Walldius reported in 2001, was the concentration of apo B proteins, reflecting the dominance of small, 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, Walldius said, because LDL cholesterol “doesn’t tell 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, Walldius said, “I’ll 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.
One key fact to remember in this discussion is that LDL and LDL cholesterol are not one and the same. The LDL carries cholesterol, but the amount of cholesterol in each LDL particle will vary. Increasing the LDL cholesterol is not the same as increasing the number of LDL particles.
There are two ways to increase the amount of cholesterol in LDL. One is to increase the amount of cholesterol secreted to begin with; the other is to decrease the rate of disposal of cholesterol once it’s been created (which is apparently what happens when we eat saturated fat). Either method will eventually result in elevated LDL cholesterol. Joseph Goldstein and Michael Brown worked out the details of the clearance-and-disposal mechanism in the 1970s, and this work won them the Nobel Prize.
As for secretion, the key point is that most low-density lipoproteins, LDL, begin their lives as very low-density lipoproteins, VLDL. (This was one implication of the observation that both LDL and VLDL are composed of the same apo B protein, and it was established beyond reasonable doubt in the 1970s.) This is why VLDL is now commonly referred to as a precursor of LDL, and LDL as a remnant of
