Lipoprotein(a) and the atherothrombotic process: mechanistic insights and clinical implications

Although many epidemiologic studies have pointed at an association between plasma levels of lipoprotein(a) (Lp(a)) and cardiovascular risk, the data obtained have been conflicting because of a number of factors, particularly those dealing with plasma storage, lack of assay standardization, population sample size, age, gender, ethnic variations, and variable disease endpoints. Moreover, the attention has been primarily focused on whole Lp(a), with relatively less emphasis on its constituent apolipoprotein(a) and on the apolipoprotein B100-containing lipoprotein, mainly low-density lipoprotein (LDL), to which apolipoprotein(a) is linked. According to recent studies, small-size apolipoprotein(a) isoforms may represent a cardiovascular risk factor either by themselves or synergistically with plasma Lp(a) concentration. Moreover, the density properties of the LDL moiety may have an impact on Lp(a) pathogenicity. It has also become apparent that Lp(a) can be modified by oxidative events and by the action of lipolytic and proteolytic enzymes with the generation of products that exhibit atherothrombogenic potential. The role of the O-glycans linked to the inter-kringle linkers of apolipoprotein(a) is also emerging. This information is raising the awareness of the pleiotropic functions of Lp(a) and is opening new vistas on pathogenetic mechanisms whose knowledge is essential for developing rational therapies against this complex cardiovascular pathogen.