Elevated sLOX-1 levels in ACS patients predict fatal events at 1 year

Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes

Literature - Kraler S, Wenzl FA, Georgiopoulos G, et al. - Eur Heart J. 2022; doi.org/10.1093/eurheartj/ehac143

Introduction and methods

Background

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is expressed by atherosclerotic plaques and has been suggested to play an important role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD) [1-3]. Pro-inflammatory conditions in the atherosclerotic plaque simulate LOX-1 cleavage and in turn, its shedding product, soluble LOX-1 (sLOX-1) is emerging as a novel biomarker which reflects plaque burden and vulnerability [4,5]. Previous studies have shown that elevated sLOX-1 plasma levels are related to poor outcomes in stable patients during long-term follow-up [6,7].

Aim of the study

The objective of this study - known as the SPUM-ACS-study – was to study the relationship of sLOX-1 with mortality from any cause at 30 days and 1 year, the interplay of sLOX-1 with hs-CRP on risk of death from any or CV causes and the association of temporal changes of sLOX-1 with plaque progression in patients with ACS.

Methods

The SPUM-ACS study was an investigator-driven, multicentre prospective cohort study [8-11]. Between January 2010 and January 2019, a total of 2747 patients with ACS (n=2639) and chronic coronary syndrome (CCS; n=69) were included in the study as well as sex- and age-matched healthy controls (CTRL; n=120).

In a subcohort of ACS patients, longitudinal sLOX-1 measurements and serial intracoronary intravascular ultrasound (IVUS) at baseline and 1 year follow-up were performed.

Main results

  • ACS patients displayed markedly elevated sLOX-1 levels compared to CCS patients and CTRL [CCS and CTRL vs ACS, 2.00 (IQR: 2.00–13.01) and 2.00 (2.00–6.93) vs. 35.08 (15.75-73.44) pg/mL, respectively, P<0.0001].
  • sLOX-1 elevations were particularly evident in patients with ST-segment elevation myocardial infarction (STEMI).
  • Plasma sLOX-1 showed weak to no correlation with hs-CRP, NT-proBNP, LDL-c and hs-TnT.
  • High sLOX-1 levels (third tertile; T3) were associated with approx. threefold increased risk of death from any cause at 30 days (T3: fully adjusted HR, 3.11, 95% CI, 1.44–10.61; P=0.0055).
  • High plasma sLOX-1 was a strong independent predictor of all-cause mortality over 1 year (T3: fully adjusted HR 2.04, 95% CI:1.19–3.92, P=0.0098), remaining consistent after adjusting the multivariable Cox model for the GRACE 2.0 score (T3: fully adjusted+GRACE 2.0 HR 1.86, 95%CI: 1.04–3.74, P=0.0391).
  • High sLOX-1 showed a pronounced association with CV mortality at 30 days (T3: adjusted HR 3.81, 95%CI:1.62-19.62,P=0.0036) and at 1 year (T3: fully adjusted HR 2.29, 95%CI: 1.19-5.34, P=0.0148).
  • Stratification according to hs-CRP and sLOX-1 showed that patient with high sLOX-1 had a consistently higher risk for death from any cause and death from CV causes.
  • In the imaging substudy, a marked interaction could be established between plasma sLOX-1 trajectories and plaque dynamics in ACS patients receiving lipid-lowering therapy, and absolute changes in plasma sLOX-1 levels showed good discrimination for predicting plaque progression during the first year after ACS (AUC=0.74; 95% CI, 0.59–0.86; P=0.0031).

Conclusion

This study showed that sLOX-1 plasma levels are increased during ACS, particularly in patients with STEMI, predicting fatal events at 1 year beyond both traditional and established risk factors as well as GRACE 2.0. Persistently high plasma levels of sLOX-1 after ACS associate with coronary plaque progression in patients receiving lipid-lowering therapy. Thus, sLOX-1 has shown to be a novel and independent biomarker for fatal events in patients presenting with ACS.

References

1. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T,et al. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atheroscleroticlesions.Circulation1999;99:3110–3117.

2. Akhmedov A, Sawamura T, Chen C-H, Kraler S, Vdovenko D, Lüscher TF. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease. Eur Heart J 2021;42:1797 1807.

3. Mentrup T, Theodorou K, Cabrera-Cabrera F, Helbig AO, Happ K, Gijbels M, et al. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. J Exp Med 2019;216:807–830.

4. Hofmann A, Brunssen C, Wolk S, Reeps C, Morawietz H. Soluble LOX-1: a novel biomarker in patients with coronary artery disease, stroke, and acute aortic dissection? J Am Heart Assoc 2020;9:e013803.

5. Barreto J, Karathanasis SK, Remaley A, Sposito AC. Role of LOX-1 (lectin-like oxidized low-density lipoprotein receptor 1) as a cardiovascular risk predictor mechanistic insight and potential clinical use. Arterioscler Thromb Vasc Biol 2021;41:153–16610

6. Markstad H, Edsfeldt A, Mattison IY, Bengtsson E, Singh P, Cavalera M, et al. High levels of soluble lectinlike oxidized low-density lipoprotein receptor-1 are associated with carotid plaque inflammation and increased risk of ischemic stroke. J Am Heart Assoc 2019;8:e009874.

7. Zhao Z-W, Xu Y-W, Li S-M, Guo J-J, Yi T, Chen L-L. Higher serum lectin-like oxidized low-density lipoprotein receptor-1 in patients with stable coronary artery disease is associated with major adverse cardiovascular events: a multicentre pilot study. Biochem Med (Zagreb) 2019;29:010705.

8. Li XS, Obeid S, Klingenberg R, Gencer B, Mach F, Räber L, et al. Gutmicrobiota-dependent trimethylamine N-oxide in acute coronary syndromes: a prognostic marker for incident cardiovascular events beyond traditional risk factors. Eur Heart J 2017;38:814–824.

9. Li XS, Obeid S, Wang Z, Hazen BJ, Li L,Wu Y, et al. Trimethyllysine, a trimethylamine N-oxide precursor, provides near-and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J 2019;40:2700–2709.

10. Laaksonen R, Ekroos K, Sysi-Aho M, Hilvo M, Vihervaara T, Kauhanen D, et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL cholesterol. Eur Heart J 2016; 37:1967–1976.

11. Klingenberg R, Aghlmandi S, Liebetrau C, Räber L, Gencer B, Nanchen D, et al. Cysteine-rich angiogenic inducer 61 (Cyr61): a novel soluble biomarker of acute myocardial injury improves risk stratification after acute coronary syndromes. Eur Heart J 2017;38:3493–3502.

Find this article online at Eur Heart J.

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