San Diego, CA - In a study of more than 500 patients who were undergoing angiography, the oxidized LDL (OxLDL)/apolipoprotein B-100 (ApoB) ratio was related to the level of Lp(a) lipoprotein, and both measures reflected the presence and degree of obstructive CAD [1]. The probability of coronary blockage was greatest among patients with high levels of these blood markers who were aged 60 or younger, especially if they also had hypercholesterolemia.

The report is published in the July 7, 2005 issue of the New England Journal of Medicine.

Lead study author Dr Sotirios Tsimikas (University of California, San Diego) told heartwire that the key findings are "first, we have a novel measure—oxidized phospholipid per ApoB—that correlates with Lp(a) lipoprotein levels and predicts the presence and extent of angiographically determined coronary artery disease. . . . Second, this suggests that Lp(a) may be atherogenic, because it binds proinflammatory oxidized phospholipids, and that may be a mechanism of atherogenesis."

Apolipoprotein B-100 is a component of Lp(a) lipoprotein. It is known that increased plasma levels of Lp(a) lipoprotein independently predict angiographically documented CAD. The team investigated whether the binding of phospholipids, specifically oxidized LDL, to ApoB reflects the extent of coronary artery blockage.

In an accompanying Perspective [2], Drs Judith Berliner and Andrew Watson (University of California, Los Angeles) write that "phospholipids are ubiquitous molecules that are important to the structural integrity of cells and lipoproteins. When oxidized, however, they can promote inflammation. . . . Studies suggest that proteins and enzymes that remove or destroy oxidized phospholipids prevent atherosclerosis."

As Tsimikas explained to heartwire, "Oxidized phospholipids are very integral in the atherogenic process. They're involved early and late, and they are present in large amounts within vulnerable plaque. If you could find a way to prevent them from accumulating in the wall, that would theoretically reduce inflammation and the impetus for developing atherosclerosis."

The team enrolled 504 consecutive patients (mean age 60.1+10.1; 61% men) who were undergoing coronary angiography at the Mayo Clinic and determined their OxLDL/ApoB ratios and Lp(a) levels.

"The measures were much more predictive in young patients," Tsimikas told heartwire. "One of the reasons that may be the case is that Lp(a) levels are determined genetically, and adult patients generally have the same level they were born with, unlike cholesterol, which rises slowly with age." About 25% of the population has elevated Lp(a) levels, and levels tend to increase during major stressful situations such as an acute MI but then decrease. Niacin can affect Lp(a) levels, but it is not very effective. An elevated OxLDL/ApoB ratio or Lp(a) level and high cholesterol puts patients at a very high risk for having coronary artery disease, particularly when they are less than 60 years old.

Test kits are currently available to measure Lp(a) clinically. Tsimikas and his team have developed a way to measure OxLDL/ApoB, which is not yet commercially available. More studies will be needed to determine whether this ratio provides independent information in addition to Lp(a) levels.

It seems that when there are additional risk factors, such as high cholesterol, Lp(a) levels provide an additional predictive value, especially among young patients. This population would be a rational choice for studying new therapeutic agents, Tsimikas said.

"I'm hoping that, ultimately, drug companies will look at Lp(a) as a target for research and find ways to reduce levels in circulation, which may translate into better clinical outcomes."