Up-regulation of LDL-receptor expression by LDL-immunoapheresis in patients with familial hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is characterized by an autos omal dominantly inherited deficiency of LDL-receptor expression on the cell surface, leading to excess plasma LDL-cholesterol and severe premature ath erosclerosis, In patients with heterozygous FH, a major therapeutic objecti ve of conventional drug therapy is to stimulate maximally the residual cell ular capacity to produce LDL-receptors via inhibition of endogenous cholest erol synthesis, in contrast, LDL-immunoapheresis aims at reducing the plasm a LDL-cholesterol level by extracorporeal elimination of LDL particles. The present study investigates whether LDL-immunoapheresis applied in addition to conventional drug therapy is able to further stimulate residual LDL-rec eptor expression capacity in patients with heterozygous FB via the withdraw al of external cholesterol supply, thereby exerting a second accessory lipi d lowering effect. Methods: LDL-receptor expression-calculated by transforming mean fluorescen ce intensities into numbers of antibody binding sites per cell (S/C)-was de termined flow-cytometrically on peripheral blood monocytes before and after LDL-apheresis, For a comparison with the maximum obtainable receptor expre ssion capacity, in vitro stimulation experiments under completely LDL defic ient conditions were performed. Results: Prior to LDL-apheresis, LDL-receptor density was comparable in pat ients (N=7; 2014 +/- 359 S/C) and controls (N=10; 1782 +/- 252 S/C), Under in vitro conditions LDL-receptor expression of controls exceeded that of pa tients with FH by 1.6 times, Immediately after apheresis, LDL-receptor expr ession significantly increased to almost the same level as obtained by in v itro stimulation (3640 +/- 423 S/C and 3632 +/- 572 S/C), The LDL-receptor expression in FH subsequent to LDL-apheresis exhibited two patterns of kine tics [Type I: maximal receptor stimulation (288 +/- 70%; P<0.07) already du ring apheresis; Type 2: highest receptor density 24 hours after treatment ( 149 +/- 11%; P<0.01)]. Conclusions: These results demonstrate that despite drug therapy, LDL-apher esis significantly stimulates the residual LDL-receptor expression in FH vi a the reduction of available extracellular cholesterol resulting in delayed reappearance of hypercholesterolemia in between treatments.