Chapter 17 - Lipoprotein(a)

Abstract

Elevated Lp(a) levels are an independent and causal risk factor for a variety of cardiovascular diseases including coronary heart disease, aortic stenosis and stroke. Since the initial report of human Lp(a) in 1963, much work has been undertaken to understand its structure, biogenesis and catabolism, and mechanism of action in disease. The Lp(a) particle consists of the unique glycoprotein apo(a) attached covalently to an low-density lipoprotein-like moiety. The cloning of a liver cDNA encoding apo(a) in 1987 revealed that apo(a) contains many repeated copies of a sequence that closely resembles plasminogen K4, followed by domains homologous to the plasminogen K5 and protease domains. The apo(a) kringle 4-like (KIV) repeats comprise 10 different subtypes based on amino acid comparison, with the KIV2 domain present in multiple identically repeated copies encoded by the LPA gene; this results in the marked isoform size heterogeneity arising from differently sized LPA alleles. Up to 90% of the variation in Lp(a) levels is accounted for by genetic factors, most residing within LPA itself. Hence, Lp(a) is the single most prevalent inherited risk factor for cardiovascular disease. Early hypotheses that the similarity between apo(a) and plasminogen results in inhibition of fibrinolysis by Lp(a) have given way to the appreciation that covalently bound oxidised phospholipids on apo(a) result in pro-inflammatory effects of Lp(a) in cardiovascular diseases. Many challenges remain before widespread clinical adoption of Lp(a), including ongoing issues with standardisation of Lp(a) measurement. Whilst several compounds are known to lower Lp(a) levels, the extent of lowering is generally insufficient and, more importantly, not specific to Lp(a). An apo(a) antisense oligonucleotide (pelacarsen), which specifically lowers Lp(a) by greater than 80%, is now in Phase III cardiovascular outcomes trials. This will allow us to finally address the question of whether targeted Lp(a) lowering reduces coronary heart disease risk.