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. 2025 Oct:409:120485.
doi: 10.1016/j.atherosclerosis.2025.120485. Epub 2025 Aug 13.

Associations of ANGPTL proteins and complexes with progression of coronary artery calcification and coronary events

Günther Silbernagel  1 , Halle Higbie  2 , Tanja Meininger  3 , Deven Lemen  2 , Hongxia Li  2 , Yan Q Chen  2 , Yi Wen  2 , Eugene Y Zhen  2 , Yue-Wei Qian  2 , Polina Korovianskaia  1 , Hans J Trampisch  4 , Hubert Scharnagl  1 , Winfried März  5 , Andreas Stang  6 , Raimund Erbel  3 , Robert J Konrad  7 , Börge Schmidt  3
Affiliations

Associations of ANGPTL proteins and complexes with progression of coronary artery calcification and coronary events

Günther Silbernagel et al. Atherosclerosis. 2025 Oct.

Abstract

Background and aims: Angiopoietin-like protein 8 (ANGPTL8) forms complexes with ANGPTL3 and ANGPTL4 to regulate lipoprotein lipase (LPL) activity, and decreased LPL activity is an established cardiovascular risk factor. Serum levels of ANGPTL4/8 and C-terminal domain-containing ANGPTL4 (CD-ANGPTL4) are positively associated with cardiovascular death, however, the underlying mechanisms remain incompletely understood. The present study investigated relationships of ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8 with coronary artery calcification (CAC) progression (using Agatston scores) and incident coronary events.

Methods: ANGPTL3, ANGPTL3/8, CD-ANGPTL4, and ANGPTL4/8, were measured using dedicated immunoassays in participants of the Heinz Nixdorf Recall (HNR) study, an unselected, population-based cohort of subjects free from cardiovascular disease at baseline. CAC measurements were performed at baseline and after 5 years in 2887 participants, and there was follow-up for coronary events (median duration 18.8 years).

Results: Median Agatston scores increased over 5 years from 6.70 (t0) to 24.75 (t1), and 315 participants experienced a coronary event. Concentrations of ANGPTL3 and ANGPTL3/8 were not associated with Agatston score progression. ANGPTL3 was associated with incident coronary events, whereas ANGPTL3/8 was not. In contrast, CD-ANGPTL4 and ANGPTL4/8 were positively associated with both Agatston score progression and incident coronary events.

Conclusions: Associations of ANGPTL3 and ANGPTL3/8 with coronary atherosclerosis progression and incident coronary events were inconsistent, while CD-ANGPTL4 and ANGPTL4/8 were associated with both coronary atherosclerosis progression and incident coronary events. Associations of ANGPTL4/8 and CD-ANGPTL4 with cardiovascular events may reflect progression of coronary atherosclerosis conferred by diabetes, inflammation, or the potential intrinsic effects of CD-ANGPTL4 and ANGPTL4/8.

Keywords: ANGPTL4/8; CD-ANGPTL4; Coronary artery calcification (CAC); Coronary event.

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Conflict of interest statement

Declaration of competing interest Y.Q.C., H.H., H.L., D.L., Y.W., E.Y.Z., Y–W.Q., and R.J.K. are Eli Lilly and Company employees and own Lilly stock. G.S. has received research funding from Numares AG, Sanofi, Bayer, and Eli Lilly, consulting fees from Sanofi, honoraria from Sanofi and Daiichi-Sankyo, meeting travel expenses from Bayer, Amgen, Daiichi-Sankyo, and research materials from Eli Lilly. H.S. has received research grants and support from Abbott Diagnostics and Amgen and honoraria from Amgen and Sanofi. W.M. has received grants from Siemens Healthineers, Boehringer Ingelheim, grants and personal fees from Aegerion, Amgen, Boehringer Ingelheim, Sanofi, Amryt Pharma, BASF, Abbott Diagnostics, Numares AG, Berlin-Chemie, Akzea Therapeutics, and Novartis, personal fees from Vifor Pharma, and employment from SYNLAB Holding Deutschland. The other authors declare no disclosures.

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