Lipoprotein(a) measurement issues: Are we making a mountain out of a molehill?

Abstract

Lipoprotein(a) [Lp(a)] became besides LDL cholesterol one of the most attractive targets for intervention in cardiovascular disease. Strong genetic evidence supports the causal association between high Lp(a) concentrations and cardiovascular outcomes. Since specific Lp(a)-lowering therapies are under clinical investigation, the interest in measuring Lp(a) has markedly increased. However, the special structure of the lead protein component of Lp(a), named apolipoprotein(a), creates difficulties for an accurate measurement of Lp(a). A highly homologous repetitive structure, called kringle IV repeat with up to more the 40 repeats, causes a highly polymorphic protein. Antibodies raised against apolipoprotein(a) are mostly directed against the repetitive structure of this protein, which complicates the measurement of Lp(a) in molar terms. Both measurements in mass (mg/dL) and molar terms (nmol/L) are described and a conversion from one into the another unit is only approximately possible. Working groups for standardization of Lp(a) measurements are going to prepare widely available and improved reference materials, which will be a major step for the measurement of Lp(a). This review discusses many aspects of the difficulties in measuring Lp(a). It tries to distinguish between academic and practical concerns and warns to make a mountain out of a molehill, which does no longer allow to see the patient behind that mountain by simply staring at the laboratory issues. On the other hand, the calibration of some assays raises major concerns, which are anything else but a molehill. This should be kept in mind and we should start measuring Lp(a) with the aim of a better risk stratification for the patient and to identify those patients who might be in urgent need for a specific Lp(a)-lowering therapy as soon as it becomes available.

Keywords: Calibrator; Isoform-sensitivity; Lp(a); Lp(a) measurement; apo(a) size polymorphism.