Lipoprotein (a) metabolism estimated by nonsteady-state kinetics.

Abstract

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle with an additional apolipoprotein named apo(a). The concentration of Lp(a) in plasma is determined to a large extent by the size of the apo(a) isoform. Because elevated Lp(a) concentrations in plasma are associated with risk for premature coronary heart disease it is important to determine whether variations in production or catabolism mediate differences in Lp(a) concentration. We determined metabolic parameters of Lp(a) in 17 patients with heterozygous familial hypercholesterolemia or severe mixed hyperlipidemia by fitting a monoexponential function to the rebound of Lp(a) plasma concentration following LDL-apheresis. In 8 of those 17 patients this was done twice following two different aphereses. Although this approach allows one to estimate metabolic parameters without the use of a tracer, it requires several major assumptions such as that apheresis itself does not change production or catabolism of Lp(a) and that Lp(a) metabolism can be described by a single compartment. One apheresis decreased Lp(a) concentration by 59.1+/-8.3%. The fractional catabolic rate (FCR) was 0.16+/-0.12 d(-1) and production rate 6.27+/-5.26 mg x kg(-1) x d(-1). However, observed (concentration before first apheresis) and predicted steady-state concentrations differed considerably (more than 20%) in 9 of 17 patients, indicating that not all assumptions were fulfilled in all patients. Production rate but not FCR was correlated with Lp(a) plasma concentration (r2 = 0.43, P = 0.004) and molecular weight of apo(a) (r2 = 0.48, P = 0.011), which confirms radiotracer experiments showing that variations in Lp(a) plasma concentrations are due to differences in production not catabolism. When parameters were estimated twice in a subgroup of eight patients, satisfactory reproducibility was observed in six patients. Although parameters determined on two occasions correlated well, only FCR was concordant (intraclass correlation coefficient). Thus, despite the limitations arising from the assumptions implicit to this method, metabolic parameters of Lp(a) can be estimated from the rebound of plasma concentration following apheresis.