Mature proprotein convertase subtilisin/kexin type 9, coronary atheroma burden, and vessel remodeling in heterozygous familial hypercholesterolemia

• Published in: Journal of clinical lipidology 2017-03, Vol.11 (2), p.413-421.e3
• Main Authors: Kataoka, Yu, Harada-Shiba, Mariko, Nakao, Kazuhiro, Nakashima, Takahiro, Kawakami, Shoji, Fujino, Masashi, Kanaya, Tomoaki, Nagai, Toshiyuki, Tahara, Yoshio, Asaumi, Yasuhide, Hori, Mika, Ogura, Masatsune, Goto, Yoichi, Noguchi, Teruo, Yasuda, Satoshi
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cholesterol, LDL - blood; Coronary Artery Disease - complications; Coronary atherosclerosis; Female; Furin - metabolism; Heterozygote; Heterozygous familial hypercholesterolemia; Humans; Hyperlipoproteinemia Type II - complications; Hyperlipoproteinemia Type II - enzymology; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - physiopathology; Intravascular ultrasound; Male; Middle Aged; Plaque, Atherosclerotic - complications; Proprotein Convertase 9 - metabolism; Proprotein convertase subtilisin/kexin type 9; Vascular Remodeling
• ISSN: 1933-2874; 1876-4789
• DOI: 10.1016/j.jacl.2017.01.005

Proprotein convertase subtilisin/kexin type 9 (PCSK9), an important contributor to low-density lipoprotein metabolism in heterozygous familial hypercholesterolemia (HeFH), exhibits direct proatherogenic effects. PCSK9 circulates as mature and furin-cleaved forms, which differ in its biological activity. However, it remains to be elucidated whether each PCSK9 subtype has different atherogenic properties. To investigate the association of each PCSK9 subtype with coronary atherosclerosis in HeFH. About 204 nonculprit segments in 138 HeFH subjects with coronary artery disease were evaluated by using intravascular ultrasound. Mature, furin-cleaved PCSK9 and total concentration of PCSK9 subtypes were measured by using enzyme-linked immunosorbent assay (BML Inc., Tokyo, Japan). The relationship of these PCSK9 values with intravascular ultrasound measures was investigated. Mature PCSK9 level was positively associated with percent atheroma volume (PAV: r = 0.78, P = .003). Despite extensive atheroma under a higher mature PCSK9 level, vessel volume did not change across any mature PCSK9 levels (r = 0.05, P = .78). These responses resulted in smaller lumen volume, which was negatively correlated to mature PCSK9 level (r = 0.65, P = .009). By contrast, there were no significant relationships of PAV with furin-cleaved (r = 0.12, P = .45) and total PCSK9 (r = 0.37, P = .25) levels. On multivariate analysis, mature PCSK9 level independently contributed to PAV (odds ratio: 1.45, 95% confidence interval: 1.11–1.67, P = .01). Even in subjects with low-density lipoprotein cholesterol level