Loss of Plasma Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) After Lipoprotein Apheresis.

Tavori H, Giunzioni I, Linton MF, Fazio S.
Circ Res. 2013 Oct 11. [Epub ahead of print]
 Patients with Familial Hypercholesterolaemia (FH) have extremely high LDL-c levels and develop premature coronary artery disease (CAD). FH patients with CAD and LDL-c above 200 mg/dl, despite maximal therapy, or when therapy is not tolerated, are eligible for lipoprotein apheresis (LA), to lower LDL-c levels. LA selectively removes apolipoprotein (apo) B-containing lipoproteins from plasma, thereby lowering LDL by 70-80% [1]. LA furthermore lowers Lp(a), triglycerides (TG) and HDL-c levels, and possibly other CAD biomarkers, depending on the LA method [2-4].
Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) regulates cell-surface LDL-receptor (LDLR) levels. Inhibition of PCSK9 is a promising therapeutic strategy to lower LDL-c [5-8]. PCSK9 has been found to associate with LDL in plasma [9-12]. It is currently unknown whether changes in LDL levels affect plasma PCSK9 levels.
PCSK9 circulates in plasma in different molecular forms, detectable as a 62 kDa band (full-length protein minus prodomain), a 55 kDa fragment (cleavage product) and higher molecular weight forms, probably homo- or hetero-multimers.
This study analysed the effect of modulating LDL levels by LA on PCSK9 plasma levels, by measuring PCKS9 levels in plasma from six FH patients before and after removal of apoB-containing lipoproteins via LA, and in the apheresis column eluate. The expected reduction of PCKS9 was 32%, based on an estimated 80% removal of LDL-c, and ~40% of PCSK9 associated with LDL.

Main results

• Plasma PCKS9 levels were significantly reduced (52+5%) following three consecutive LA treatment cycles, while control parameters (albumin, creatinin) were not affected.
  PCSK9 levels returned to pre-treatment values between each cycle.
  LDL-c and PCSK9 decreases were significantly correlated (r²=0.26, P=0.0322).
• 81+11% of the PCSK9 was removed from the LDL-bound fraction, and 48+14% from the apoB-free fraction of plasma, explaining the higher than predicted PCSK9 reduction.
  PCSK9 bound to LDL was exclusively in the 62 kDa monomeric active form, while different molecular forms were detected in the apoB-free fraction (mainly the smaller 55 kDa form).

Conclusion

This study demonstrates that PCSK9 is removed from the circulation during lipoprotein apheresis, via both LDL-dependent and LDL-independent mechanisms. The PCKS9-lowering effect of LA may explain part of the prolonged decline of LDL-c levels after each apheresis. Thus, the reported correlation between PCSK9 and LDL-c or apoB levels is not only due to the effect of PCSK9 on LDLr, but also depends on the physical association between PCSK9 and LDL. LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden for FH patients.
Only the intact PCSK9 isoform was found to be bound to LDL-c, implying that this might be the only form with affinity for LDL-c, or the binding to LDL-c may protect it from cleavage and multimerization.

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