Author + information
- Bruce A. Kottke, MDa
I am writing you regarding an article by von Eckardstein et al. published in JACC, Vol. 37, pp. 434–9, 2001, on “Lipoprotein(a) Further Increases the Risk of Coronary Events in Men With High Global Cardiovascular Risk.” The authors are to be complimented for conducting a large study using their PROCAM population where they were able to obtain a long follow-up and also for making the measurements in fresh serum, which reduces many of the errors previously seen in Lp(a) assays.
However, despite these precautions, the study still has a major problem. In their article, Lp(a) is measured in the units of g/l. These units have little meaning in terms of the quantity of Lp(a) present in the plasma, as the (a) of Lp(a) is noted to have a molecular weight that can vary between 250,000 and 750,000 daltons. This variation is determined by a total of over 30 genetically determined alleles. Thus, there are 30 × 30, or 900 possible variations in the molecular weight of this protein in the patient’s plasma, and each patient will have the possibility of any two of these 900 combinations. With this marked variation in molecular weight, it is impossible to calculate the true concentrations of this protein in terms of g/l. To do so, one must assume an average molecular weight for the compound. This is very difficult because the distribution of variation in the size of the compound is not random, but is well-known to vary widely in different racial populations. The only solution to this problem is to use an assay that measures Lp(a) in units of millimoles per liter. This can be done either by using antibodies that react only with the nonrepeating portions of the (a) sequence (i.e., those regions not included in kringle IV) or by capturing the particles with antibodies to (a) and detecting with antibodies to apo B. Methods for using these techniques have been published previously.
It is unfortunate that in this large study these methods were not utilized. As a result, the data are very difficult to interpret because they represent variations of two factors: 1) variation in the size of (a), which may well be related to disease and which would be reflected indirectly in the concentrations measured by methods using a g/l unit; or 2) variation in the concentration of particles of Lp (a) in the plasma, which may be determined by many other clinical factors.
It is unfortunate that these methods have become utilized extensively in the literature. They are leading to a great deal of confusion and actually represent biochemical artifacts. Until we get a reasonable standardization of Lp(a) assays, it is very difficult to interpret any studies such as those reported in the article by Von Eckardstein et al. I would make a plea for people working in this area to get together to develop a true measure of the Lp(a) that is not affected by variations in the molecular size of (a). When such is done, we can then determine which clinical factors are related to variations in the concentration of Lp(a) particles (the number of particles/ml) versus those that are related to genetically determined differences in the size of (a).
- American College of Cardiology