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The impact of gene variants on the thickness and softness of the Achilles tendon in familial hypercholesterolemia

  • Masahito Michikura
    Affiliations
    Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

    Department of Endocrinology and Metabolism, National Cerebral and Cardiovascular Center Hospital, Suita, Japan

    Cardiovascular Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
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  • Mika Hori
    Correspondence
    Corresponding author. Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
    Affiliations
    Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

    Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

    Department of Endocrinology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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  • Masatsune Ogura
    Affiliations
    Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

    Department of General Medical Science, Chiba University Graduate School of Medicine, Chiba, Japan
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  • Kiminori Hosoda
    Affiliations
    Department of Endocrinology and Metabolism, National Cerebral and Cardiovascular Center Hospital, Suita, Japan

    Laboratory of Clinical Genetics, National Cerebral and Cardiovascular Center, Suita, Japan
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  • Mariko Harada-Shiba
    Affiliations
    Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan

    Cardiovascular Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
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      Highlights

      • The proportion of patients with LDLR variants increased with increases in Achilles tendon (AT) thickness/softness.
      • LDLR variants affected the AT thickness and softness independent of the LDL-C year score.
      • PCSK9 variants did not influence AT thickening and softening or the prevalence of coronary artery disease (CAD).
      • Evaluating AT is important to identify familial hypercholesterolemia (FH) patients with LDLR variants at high risk for CAD.

      Abstract

      Background and aims

      Familial hypercholesterolemia (FH) is characterized by high low-density lipoprotein (LDL)-cholesterol, xanthoma of the Achilles tendon (AT), and premature coronary artery disease (CAD). Ultrasonography can assess AT thickness and softness, making it useful for evaluating AT in FH diagnosis. We aimed to clarify whether FH-causative LDLR or PCSK9 variants affect AT thickness or softness.

      Methods

      In total, 248 FH and 60 non-familial hypercholesterolemia (non-FH) patients (total: 308) aged ≥30 years were enrolled. Patients with FH were classified according to genotype. AT thickness and elasticity index (EI) as softness were measured by ultrasonography.

      Results

      In FH patients with LDLR variants, AT was significantly thicker and softer than it was in FH patients with PCSK9 variants, FH patients without LDLR or PCSK9 variants, and patients with non-FH. The proportion of patients harboring LDLR variants significantly increased with AT thickness (p = 2.0 × 10−31) and softness (p = 1.4 × 10−18). Among those with AT thickness>8.5 mm and EI < 3.9, patients with LDLR variants accounted for 89% and 83%, respectively. The odds of AT thickening, AT softening and CAD increased 13.3-fold, 4.9-fold, and 2.1-fold, adjusted for the LDL-C year score by the presence of LDLR variants compared with those of patients without LDLR or PCSK9 variants. PCSK9 variants did not influence AT thickening or softening or CAD prevalence.

      Conclusions

      LDLR variants affected AT thickness and softness independent of the LDL-C year score, but PCSK9 variants did not. Evaluating AT is important for identifying FH patients with LDLR variants at high risk for CAD.

      Graphical abstract

      Keywords

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