Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis

Hagai Tavori, Ilaria Giunzioni, MacRae F. Linton, Sergio Fazio

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77±4%). Concomitantly, PCSK9 levels fell by 52±5%, strongly correlating with the LDL drop (P=0.0322; r=0.26), but not with decreases in triglyceride (49±13%) or high-density lipoprotein levels (18±2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81±11% of LDL-bound PCSK9 and 48±14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.

    Original languageEnglish (US)
    Pages (from-to)1290-1295
    Number of pages6
    JournalCirculation Research
    Volume113
    Issue number12
    DOIs
    StatePublished - Dec 6 2013

    Fingerprint

    Proprotein Convertases
    Subtilisin
    Blood Component Removal
    Lipoproteins
    LDL Lipoproteins
    Hyperlipoproteinemia Type II
    Apolipoproteins B
    Proprotein Convertase 1
    Therapeutics
    Dextran Sulfate
    HDL Lipoproteins
    Cellulose

    Keywords

    • cholesterol
    • familial hypercholesterolemia
    • lipoprotein apheresis, LDL
    • PCSK9

    ASJC Scopus subject areas

    • Physiology
    • Cardiology and Cardiovascular Medicine

    Cite this

    Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis. / Tavori, Hagai; Giunzioni, Ilaria; Linton, MacRae F.; Fazio, Sergio.

    In: Circulation Research, Vol. 113, No. 12, 06.12.2013, p. 1290-1295.

    Research output: Contribution to journalArticle

    @article{8743369f41994e9b81ffd26c953f9082,
    title = "Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis",
    abstract = "RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30{\%} of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77±4{\%}). Concomitantly, PCSK9 levels fell by 52±5{\%}, strongly correlating with the LDL drop (P=0.0322; r=0.26), but not with decreases in triglyceride (49±13{\%}) or high-density lipoprotein levels (18±2{\%}). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81±11{\%} of LDL-bound PCSK9 and 48±14{\%} of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.",
    keywords = "cholesterol, familial hypercholesterolemia, lipoprotein apheresis, LDL, PCSK9",
    author = "Hagai Tavori and Ilaria Giunzioni and Linton, {MacRae F.} and Sergio Fazio",
    year = "2013",
    month = "12",
    day = "6",
    doi = "10.1161/CIRCRESAHA.113.302655",
    language = "English (US)",
    volume = "113",
    pages = "1290--1295",
    journal = "Circulation Research",
    issn = "0009-7330",
    publisher = "Lippincott Williams and Wilkins",
    number = "12",

    }

    TY - JOUR

    T1 - Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis

    AU - Tavori, Hagai

    AU - Giunzioni, Ilaria

    AU - Linton, MacRae F.

    AU - Fazio, Sergio

    PY - 2013/12/6

    Y1 - 2013/12/6

    N2 - RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77±4%). Concomitantly, PCSK9 levels fell by 52±5%, strongly correlating with the LDL drop (P=0.0322; r=0.26), but not with decreases in triglyceride (49±13%) or high-density lipoprotein levels (18±2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81±11% of LDL-bound PCSK9 and 48±14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.

    AB - RATIONALE: Lipoprotein apheresis (LA) reduces low-density lipoprotein (LDL) levels in patients with severe familial hypercholesterolemia (FH). We have recently reported that >30% of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) is bound to LDL, thus we predicted that LA would also reduce plasma PCSK9 levels by removing LDL. OBJECTIVE: Pre- and post-apheresis plasma from 6 patients with familial hypercholesterolemia on 3 consecutive treatment cycles was used to determine changes in PCSK9 levels. METHODS AND RESULTS: LA drastically reduced plasma LDL (by 77±4%). Concomitantly, PCSK9 levels fell by 52±5%, strongly correlating with the LDL drop (P=0.0322; r=0.26), but not with decreases in triglyceride (49±13%) or high-density lipoprotein levels (18±2%). Levels of albumin, creatinine, and CK-MB did not show significant changes after LA. Similar to LDL, PCSK9 levels returned to pretreatment values between cycles (2-week intervals). Fractionation of pre- and post-apheresis plasma showed that 81±11% of LDL-bound PCSK9 and 48±14% of apolipoprotein B-free PCSK9 were removed. Separation of whole plasma, purified LDL, or the apolipoprotein B-free fraction through a scaled-down, experimental dextran sulfate cellulose beads column produced similar results. CONCLUSIONS: Our results show, for the first time, that modulation of LDL levels by LA directly affects plasma PCSK9 levels, and suggest that PCSK9 reduction is an additional benefit of LA. Because the loss of PCSK9 could contribute to the LDL-lowering effect of LA, then (1) anti-PCSK9 therapies may reduce frequency of LA in patients currently approved for therapy, and (2) LA and anti-PCSK9 therapies may be used synergistically to reduce treatment burden.

    KW - cholesterol

    KW - familial hypercholesterolemia

    KW - lipoprotein apheresis, LDL

    KW - PCSK9

    UR - http://www.scopus.com/inward/record.url?scp=84890425649&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=84890425649&partnerID=8YFLogxK

    U2 - 10.1161/CIRCRESAHA.113.302655

    DO - 10.1161/CIRCRESAHA.113.302655

    M3 - Article

    C2 - 24122718

    AN - SCOPUS:84890425649

    VL - 113

    SP - 1290

    EP - 1295

    JO - Circulation Research

    JF - Circulation Research

    SN - 0009-7330

    IS - 12

    ER -