Lipoprotein (a) metabolism estimated by nonsteady-state kinetics

Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle with an additional apolipoprotein named apo(a). The concentration of Lp(a) in plas ma is determined to a large extent by the size of the apo(a) isoform. Becau se elevated Lp(a) concentrations in plasma are associated with risk for pre mature coronary heart disease it is important to determine whether variatio ns in production or catabolism mediate differences in Lp(a) concentration. We determined metabolic parameters of Lp(a) in 17 patients with heterozygou s familial hypercholesterolemia or severe mixed hyperlipidemia by fitting a monoexponential function to the rebound of Lp(a) plasma concentration foll owing LDL-apheresis. In 8 of those 17 patients this was done twice followin g two different aphereses. Although this approach allows one to estimate me tabolic parameters without the use of a tracer, it requires several major a ssumptions such as that apheresis itself does not change production or cata bolism of Lp(a) and that Lp(a) metabolism can be described by a single comp artment. 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.kg(-1).d(-1). However, observed (concentration before fir st apheresis) and predicted steady-state concentrations differed considerab ly (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 (r(2) = 0.43, P = 0.004) and molecular wei ght of apo(a) (r(2) = 0.48, P = 0.011), which confirms radiotracer experime nts showing that variations in Lp(a) plasma concentrations are due to diffe rences in production not catabolism. When parameters were estimated twice i n a subgroup of eight patients, satisfactory reproducibility was observed i n six patients. Although parameters determined on two occasions correlated well, only FCR was concordant (intraclass correlation coefficient). Thus, d espite 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.