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Lipoprotein(a) or Lp(a) was discovered by Kare Berg 50 years ago.1 It was he who described its two main features, namely that high levels were inherited and that these were associated with premature cardiovascular disease (CVD). Since then it has been regarded as an intriguing analogue of low density lipoprotein (LDL), present in plasma in much lower concentrations than LDL but lacking in proof of pathogenicity. However, recently published seminal studies have unequivocally established the role of Lp(a) as a causal and independent risk factor for CVD.2 Other studies suggest, but with less certainty, that therapeutic lowering of Lp(a) may be beneficial. Here we outline the reasons why Lp(a) should be taken seriously and measured more frequently than hitherto, using appropriate methods.
Structure and metabolism
Lp(a) consists of an LDL particle to which is attached a glycoprotein, apolipoprotein(a) or apo(a), covalently linked to the apolipoprotein B (apoB) moiety of LDL by a disulphide bond. The presence of apo(a) increases the density of Lp(a) compared with LDL and greatly reduces its affinity for the LDL receptor. This presumably explains why raised Lp(a) levels in plasma are unaffected by statins, which increase hepatic LDL receptor activity. Apo(a) has close structural similarity with plasminogen, which endows Lp(a) with antifibrinolytic properties via its competitive inhibition of tissue-type plasminogen activator—mediated activation of plasminogen. This, allied with its LDL-like features, gives Lp(a) the potential for promoting both atherosclerosis and thrombosis.
Apo(a) consists of a number of pleated structures, so-called Kringles, one of which, Kringle IV type 2 is repeated a variable number of times from 2 to >40; this gives rise to considerable differences in the size and molecular weight of apo(a) between individuals, the number of repeats being determined by the size of the apo(a) gene.2 Lp(a) levels are thus largely genetically determined, being unaltered by …
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