Report of the National Heart, Lung, And Blood Institute Workshop on Lipoprotein(A) and Cardiovascular Disease: Recent Advances and Future Directions (Special Report) (Clinical Report‪)‬

Lipoprotein(a) [Lp(a)] [4] first discovered by Kare Berg in 1963 (1), is a specific class of lipoprotein particles found in human plasma. The protein moiety comprises two components, a single copy of apolipoprotein B-100 linked to a single copy of a protein referred to as apolipoprotein(a) [apo(a)]. Treatment of Lp(a) with reducing agents yields apo(a) and a lipoprotein particle that is essentially indistinguishable from LDL, both in structure and in its physical and chemical properties. Because Lp(a) and LDL are metabolically distinct, it is evident that the special characteristics of Lp(a), including its size and density heterogeneity, are almost entirely attributable to apo(a). apo(a) is a carbohydrate-rich, highly hydrophilic protein characterized by a marked size heterogeneity that is primarily attributable to a genetic size polymorphism of the polypeptide chain (2). Numerous studies have documented that high plasma Lp(a) concentrations are associated with a variety of cardiovascular disorders, including peripheral vascular disease, cerebrovascular disease, and premature coronary disease [for a review, see Ref. (3)]. However, despite intense scientific efforts, Lp(a) continues to be an enigmatic lipoprotein particle that has defied the ability of scientists to elucidate its physiologic role and its pathologic mechanisms of action, thus making it difficult for clinicians to develop effective interventions in clinical practice. Although the mechanism of Lp(a) pathogenicity in the process of atherosclerosis remains unclear, it has been well established that Lp(a) is deposited at sites of vascular injury (4-6). As such, it is reasonable to postulate that the contribution of Lp(a) to atherosclerosis is facilitated by interactions of apo(a) with plaque elements. Analysis of an apo(a) cDNA from a human liver library in 1987 revealed that apo(a) bears striking homology with the fibrinolytic proenzyme plasminogen and is a member of the plasminogen gene superfamily (7). apo(a) contains domains that correspond to single copies of plasminogen kringle 5 and the serine protease domain, as well as multiple copies of a sequence that closely resembles plasminogen kringle 4. On the basis of amino acid sequencing, apo(a) contains 10 types of plasminogen kringle 4-like motifs (designated K4 types 1-10). Each K4 motif is present in a single copy, except for apo(a) K4 type 2, which is present in a variable number of identically repeated copies (3 to 40) (8, 9). This forms the molecular basis of the Lp(a) isoform size heterogeneity that is a hallmark of this unique lipoprotein. It is noteworthy that despite a high degree of sequence similarity, the serine protease-like domain of apo(a) is catalytically inactive (10), which has led to speculation that Lp(a) can interfere with the physiologic functions of plasminogen in the fibrinolytic cascade. This could provide a direct link between the processes of atherosclerosis and thrombosis.