Background/Purpose: This study aims to:

1) Characterize the circulating lipidomic and proteomic profiles of APS patient and analyse its association with clinical features.

2) Investigate the short-term effects of ubiquinol supplementation (reduced coenzyme Q10).

3) Asses in vitro the impact of the circulating molecular alterations on the activity and molecular profiles of macrophages and endothelial cells.

Methods: 129 primary APS patients and 43 healthy donors (HD) underwent clinical and molecular characterization. Serum levels of 92 cardiovascular-related proteins were assessed using proximity extension assay (PEA, Olink/Cobiomic). Serum lipidomic profile was evaluated using nuclear magnetic resonance (NMR) metabolomics ( >250 metabolites, Nightingale). Unsupervised clustering analysis was conducted to stratify patients based on molecular and clinical features. Changes in the molecular profiles of 15 APS patients receiving Ubiquinol supplementation for 1 month were evaluated (NCT02218476 trial). In vitro studies exposed macrophages from HD and endothelial cells (HUVEC) to serum from APS patients combined with CoQ to asses their functional impact.

Results: Proteomic analysis identified 33 altered CVD-related proteins in APS serum compared to HD, directly associated with key clinical features such as thrombosis, autoinmmunity, thrombotic risk score (aGAPSS), etc. Besides, APS patients exhibited significant alterations in 53 metabolites, including reduced atheroprotective lipids (HDL, sphingomyelins, and phospholipids), as well as increased pro-atherogenic mediators (VLDL, LDL). Unsupervised clustering analysis identified two patient subgroups. Cluster 2 (C2), compared to cluster 1 (C1), had higher levels of VLDL, LDL, triglycerides, fatty acids, etc., and higher prevalence of arterial thrombosis, elevated aGAPSS ( >9), and traditional CVD risk factors. Interestingly, several correlations among altered proteins and metabolities were indentified.
In vivo Ubiquinol treatment partially reversed altered lipidomic and proteomic profiles in APS patients, reducing pro-atherogenic and increasing anti-atherogenic markers.
In vitro, pre-treating macrophages and HUVECs with CoQ prior to exposing them to serum from APS patients belonging to the highest CVD risk cluster (C2), prevented the induced alteration of CVD markers in both cell types as well as formation of foam cells in monocytes. 

Conclusion: 1. APS patients display an altered lipidomic and proteomic profile directly associated with an increased CVD risk.

2. In vivo, ubiquinol supplementation restored disrupted circulating lipidomic and proteomic profiles in AP patients, highlighting its cardiovascular benefits.

3. In vitro studies revealed that the altered molecular profiles of APS patients amplify the pro-atherogenic profile of macrophages and HUVECs, which was mitigated by CoQ supplementation.
Fundings: PI21/0591 & CD21/00187 funded by ISCIII and the European Union. RD21/0002/0033 funded by ISCIII and by the European Union-NextGeneration EU, via Plan de Recuperación, Transformación y Resiliencia (PRTR). RYC2021-033828-I. PID2022-141500OA-100.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-lipidomic-and-proteomic-profiles-in-antiphospholipid-syndrome-patients-are-intricately-linked-to-disease-pathogenesis-and-modulated-by-ubiquinol-supplementation/