Good Calories, Bad Calories

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 VLDL. If the liver synthesizes more cholesterol, we end up with more total cholesterol and so more LDL cholesterol, although apparently not more LDL particles. If the liver synthesizes and secretes more VLDL, we will also end up with more LDL cholesterol but we have more LDL particles as well, and they’ll be smaller and denser.