Lipoprotein(a) Concentration and Apolipoprotein(a) Size

Abstract

Espite more than 3 decades of intense scientific research that has fostered our understanding of the structure and biochemistry of lipoprotein(a) (Lp(a)), the physiopatho- logical role of Lp(a) is still poorly understood. Consequently, despite its recognition as a risk factor for coronary artery disease (CAD), the role of Lp(a) in atherogenesis and the extent to which Lp(a) levels should be assessed in clinical practice remain controversial. Lp(a), which is the most complex and poly- morphic of the lipoprotein particles, is formed by an LDL moiety and a unique protein, apo(a), linked to apolipoprotein (apo) B-100 of LDL.1 The most intriguing feature of apo(a) is that it shares an extensive structural homology with plasmino- gen, a key proenzyme of the fibrinolytic cascade. Kringle V and the protease domains of apo(a) share .85% amino-acid identity with the corresponding plasminogen domains, even though the protease domain of apo(a) does not appear to have a catalytic function. Apo(a) contains 10 different types of a sequence with variable degrees of homology with plasminogen kringle IV. The number of kringle IV type 2 repeats, which is encoded by a varying number of copies in the apo(a) gene,2 varies both within and among individuals, and at least 35 apo(a) size isoforms have been detected in human plasma.3 Despite the presence of LDL, apo(a) imparts to Lp(a) unique properties with respect to synthesis and catabolism. In fact, apo B-100 in Lp(a) particles does not appear to mediate the catabolism of this lipoprotein via the LDL receptor, thus suggesting that the attachment to apo(a) produces a steric hindrance and/or a conformational change of apo B-100. Whereas the rate of removal from the circulation determines the level of LDL, evidence has been provided that the rate of synthesis is the primary determinant of Lp(a) levels. Plasma Lp(a) concentration is primarily controlled at the level of the gene that encodes apo(a), and an inverse correlation has been shown between plasma Lp(a) concentration and apo(a) size that may arise, at least in part, from the relatively inefficient secretion of the larger apo(a) isoforms from the hepatocytes. Additionally, in contrast to LDL, the level of Lp(a) in human plasma is largely unaffected by diet, physical activity, and conventional hypolipi- demic therapy. See p 1154 Since its discovery, Lp(a) has been recognized as a risk factor for CAD, and in the majority of case-control studies, Lp(a) concentrations have been found to be higher in patients with existing CAD than in matched control subjects (re- viewed in Reference 4). The results of the prospective studies performed over the past decade have also shown that Lp(a) is a predictor of CAD, even though some of the studies of this design have failed to show a statistically significant differ- ence in Lp(a) levels between subjects who subsequently developed CAD and those who did not (reviewed in Refer- ence 4). The major reasons for the discrepant results of the prospective studies have been attributed to variations in study design, collection and storage of samples, methods used for statistical analysis, and population differences that reflect the known ethnic variability in the distribution of Lp(a) levels and apo(a) size isoforms.5,6 Additionally, it has been demon- strated that apo(a) size heterogeneity greatly affects the accuracy of Lp(a) analytical methods if the assay is based on antibodies that recognize the variably repeated kringle IV type 2. It has been shown that Lp(a) values can be substan- tially underestimated or overestimated based on apo(a) size. 7 This can have a great effect on the interpretation of clinical studies if the distribution of apo(a) size isoforms is different between patients and control subjects.