Molecular analysis of apo(a) fragmentation in polygenic hypercholesterolemia - Characterization of a new plasma fragment pattern

Hypercholesterolemia is frequently associated with elevated Lp(a) levels, a n independent risk factor for coronary, cerebrovascular, and peripheral vas cular disease. A portion of apolipoprotein(a) [apo(a)] circulates as a seri es of fragments derived from the N-terminal region of apo(a). The relations hip of elevated lipoprotein(a) [Lp(a)] levels to those of circulating apo(a ) fragments in polygenic hypercholesterolemia is indeterminate. Therefore, plasma Lp(a) and plasma and urinary apo(a) fragment levels were measured by ELISA in 82 patients with polygenic type Ha hypercholesterolemia (low dens ity lipoprotein cholesterol greater than or equal to4.13 mmol/L and triglyc erides <2.24 mmol/L) and in 90 normolipidemic subjects. Lp(a) levels were s ignificantly elevated in patients compared with control subjects (0.35 +/-0 .4 and 0.24 +/-0.31 mg/mL, respectively; median 0.13 and 0.11 mg/mL, respec tively; P=0.039), although apo(a) isoform distribution did not differ. Pati ents displayed significantly higher plasma and urinary apo(a) fragment leve ls than did control subjects (respective values were as follows: 4.97 +/-5. 51 and 2.15 +/-2.57 [median 2.85 and 1.17] mug/mL in plasma, P <0.0001; 75 +/- 86 and 40 +/- 57 [median 38 and 17] ng/mg urinary creatinine in urine, P <0.0001). The ratio of plasma apo(a) fragments to Lp(a) levels was also s ignificantly higher in patients than in control subjects (1.93 +/-1.5% and 1.75 +/-2.36%, respectively; P <0.0001). We conclude that increased plasma Lp(a) levels in polygenic hypercholesterolemia are associated with elevated circulating levels of apo(a) fragments but that this increase is not due t o decreased renal clearance of apo(a) fragments. Furthermore, we identified a new pattern of apo(a) fragmentation characterized by the predominance of a fragment band whose size was related to that of the parent apo(a) isofor m and that was superimposed on the series of fragments described previously by Mooser et al (J Clin Invest. 1996;98:2414-2424). This new pattern was a ssociated with small apo(a) isoforms and did not discriminate between hyper cholesterolemic and normal subjects. However, this new apo(a) fragment patt ern may constitute a novel marker for cardiovascular risk.