**Lipoprotein(a) — A Hallmark in Atherosclerosis and Cardiovascular Diseases**

Indumathi Chennamsetty and Gert M. Kostner

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/61078

### **Abstract**

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein (LDL)-like core and apo(a), a large molecular weight glycoprotein. Apo(a) is highly homologous to plas‐ minogen, yet in contrast exhibits a unique size polymorphism that is characterized by an increasing number of kringle-IV (K-IV) repeats. The number of K-IV repeats ranges from n = 2 to n = 40 or even higher. Apo(a) is synthesized almost exclusively in the liver and there is still some debate whether the assembly of Lp(a) from LDL and apo(a) occurs inside the liver cells or in the circulating blood. The plasma Lp(a) con‐ centration is markedly skewed reaching from <1 mg/dl up to >200 mg/dl. The plasma concentration is >90% genetically determined and correlates negatively with the num‐ ber of K-IV repeats. In the apo(a) promoter, there are numerous response elements for transcription factors and nuclear receptors that regulate apo(a) expression. The HNF4α binding sequence appears to be the most important one in that respect, yet further work needs to be done to unravel the key features of apo(a) biosynthesis un‐ der different conditions. Importantly, activation of FXR causes the dissociation of HNF4α α from its response element and in turn a significant downregulation of apo(a) transcription.

Undoubtedly, Lp(a) is one of the most atherogenic lipoproteins and recent large epi‐ demiological studies document quite impressively that Lp(a) is an independent causal risk factor for coronary heart disease (CHD) and myocardial infarction. This fact led to the development of specific medications to reduce Lp(a) in patients with high plas‐ ma concentrations. Among the registered lipid-lowering drugs, only nicotinic acid has a consistently significant Lp(a)-lowering effect, and we recently succeeded in elucidat‐ ing the mode of action of this drug. There are numerous medications in the pipeline for the treatment of hyper-Lp(a). Among those that are currently in clinical trials, CETP inhibitors, PCSK9 antibodies, MTP inhibitors as well as antisense oligonucleoti‐ des (ASO), such as the specific APO(a)Rx® from ISIS, which is directed against apo(a) mRNA and appears to be the most promising drug as it lowers Lp(a) levels by more than 90%.

Lp(a) emerged as an important screening parameter to assess coronary atherosclerosis risk. Its quantitation in the clinical laboratory was, for a long time, quite problematic

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since commonly accepted reference materials and standardized analytical methods were lacking. However, newer commercial assays based on nephelometry or tur‐ bidimetry, or ELISA using monoclonal antibodies that recognize single epitopes in apo(a), warrant comparable interlaboratory results.

**Keywords:** Metabolism, Fibrinolysis, Reference values, Medication
