Lipoprotein(a): when to measure, how to treat?

Abstract

Abstract: Lipoprotein(a) [Lp(a)] is one of the most atherogenic lipoproteins consisting of a core low-density lipoprotein particle and the specific glycoprotein apo(a). Apo(a) is homologous to plasminogen yet in contrast exhibits a specific size polymorphism. This polymorphism is due to the fact that the number of kringle-IV (K-IV) repeats ranges between two and approximately 50. Apo(a) is synthesized almost exclusively in the liver, and there is still some discussion regarding whether the assembly of Lp(a) occurs intracellularly or in the circulating blood. The plasma Lp(a) concentration is markedly skewed to the right and extends from <1 mg/dL to more than 200 mg/dL. Up to 90% of the variance of Lp(a) concentrations may be genetically determined and the Lp(a) concentration correlates inversely with the number of K-IV repeats. In the apo(a) promoter there are numerous response elements for transcription factors and nuclear receptors, whereby the HNF4α binding sequence is the most important one. Activation of FXR causes the dissociation of HNF4α from its response element and in turn a significant down regulation of apo(a) transcription. Recent large epidemiological studies document beyond any doubt that Lp(a) is an independent causal risk factor for coronary heart disease and myocardial infarction. Hence, novel approaches to correct elevated Lp(a) are under investigation. Among the established lipid-lowering drugs, only nicotinic acid lowers Lp(a) in a consistent and clinically relevant fashion, and we recently elucidated the molecular mechanism underlying this effect. Novel medicines in clinical trials include CETP inhibitors, PCSK9 antibodies, the MTP inhibitor lomitapide and antisense oligonucleotides. APO(a)Rx ®, an antisense oligonucleotide, which is specifically directed against the mRNA for apo(a), has the strongest effect on Lp(a). It offers the opportunity to examine the impact of selective Lp(a) lowering on clinical events. Lp(a) emerged as an important screening parameter to assess the risk for atherosclerosis. Its quantitation in the clinical laboratory had not been standardized for a long period of time. New commercial methods, in particular enzyme immunoassays with monoclonal antibodies that recognize single epitopes in apo(a), or nephelometric and turbidimetric assays hold the potential to warrant comparable results in different laboratories.