Abstract 10252: Lipoprotein (a) in Familial Hypercholesterolemia With Proprotein Convertase Subtilisin Kexin Type 9 Gain-of-function Mutations

Background: Lipoprotein (a) [Lp(a)] is an established residual risk factor for cardiovascular disease. In contrast to statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce Lp(a) by as much as 30%, but the mechanism remains unclear. Currently, no data exists regarding direct comparisons of serum Lp(a) levels between patients with familial hypercholesterolemia (FH) caused either by LDL receptor (LDLR) or PCSK9 mutations, which could reveal the role of PCSK9 in human Lp(a) metabolism. Methods and Results: Forty-two mutation-determined heterozygous FH patients with a PCSK9 gain-of-function mutation (FH-PCSK9, mean age=52, mean LDL-C=235 mg/dl), 198 mutation-determined heterozygous FH patients with a LDLR mutation (FH-LDLR, mean age=44, mean LDL-C=217 mg/dl), and 4,015 controls (CONTROL, mean age=56, mean LDL-C=109 mg/dl) were evaluated. We assessed their Lp(a), TC, triglyceride, HDL-C, LDL-C, use of statins, presence of hypertension, diabetes, chronic kidney disease, smoking, body mass index (BMI) and coronary artery disease. Multiple regression analysis showed that HDL-C, the use of statins, the presence of hypertension, smoking, BMI, and Lp(a) were independently associated with the presence of coronary artery disease overall. The serum level of Lp(a) in FH-LDLR was significantly higher than that of the CONTROL (median Lp(a)=11.8 mg/dl [IQR:6.5-29.4] vs 21.9 mg/dl [IQR:10.0-34.2], respectively, p=2х10-7). However, there was no significant difference between the serum level of Lp(a) in FH-LDLR and that of FH-PCSK9 (median Lp(a)=21.9 mg/dl [IQR:10.0-34.2] vs 21.1 mg/dl [IQR:11.7-34.9], respectively). Conclusion: These data suggest that Lp(a) is mainly catabolized via the LDL receptor. A significant paradox between statins and PCSK9 inhibitors in terms of Lp(a) catabolism remains.