The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) is a key scavenger receptor for oxidized low-density lipoprotein cholesterol (oxLDL), which promotes inflammation and atherosclerosis. Here we evaluated MEDI6570, an antibody that acts as a LOX-1 antagonist, in a randomized, double-blind, dose-finding study in patients with myocardial infarction (MI) and residual inflammation (high-sensitivity C-reactive protein ≥ 1 mg l-1). At 30-365 days after MI, 423 patients (75 women, 348 men) were randomly allocated to 50 mg, 150 mg or 400 mg MEDI6570 or placebo treatment subcutaneously every 4 weeks for 32 weeks. The primary endpoint, the change in the noncalcified plaque volume in the most diseased coronary segment (NCPVMD) by computed tomography angiography, was not significantly different between placebo and MEDI6570 at any dose. The secondary endpoints, global NCPV and low-attenuation plaque volume, were also not different between placebo and MEDI6570 at any dose (all placebo-adjusted comparisons, P > 0.05). With regard to exploratory endpoints, there were reductions in free soluble LOX-1 (sLOX-1) from baseline by 44.8%, 85.8%, 94.0% and 96.4% in the placebo, 50 mg, 150 mg and 400 mg dose arms, respectively (all placebo-adjusted comparisons P < 0.001). Interleukin-6 (IL-6) levels decreased by 2.9%, -3.0%, 18.9% and 21.5% in the placebo, 50 mg, 150 mg and 400 mg arms, respectively, with substantial placebo-adjusted reductions observed only at 150 mg and 400 mg (P < 0.05). MEDI6570 was well tolerated and rates of serious adverse events were similar in the MEDI6570 and placebo groups. In summary, despite favorable effects on sLOX-1 and IL-6, a LOX-1 inhibitor did not reduce noncalcified coronary plaque volume in patients with residual inflammation after acute MI. EudraCT registration: 2020-000840-75 .

Academic Affairs Cedars Sinai Health System Los Angeles CA USA

Canisius Wilhelmina Ziekenhuis Nijmegen the Netherlands

Cardiothoracic Department Freeman Hospital Newcastle upon Tyne UK

Department of Cardiology Hirakata Kohsai Hospital Hirakata Japan

Department of Cardiology Military Hospital Budapest Hungary

Department of Internal Medicine Metabolism and Gerontology University Hospital Hradec Králové Hradec Králové Czech Republic

Department of Medicine and Surgery University of Parma Parma Italy

DF Star Hospital Brasília Brazil

Division of Cardiology and Structural Heart Disease Medical University of Silesia Katowice Poland

Division of Cardiology Azienda Ospedaliero Universitaria di Parma Parma Italy

Early Clinical Development Research and Early Development Cardiovascular Renal and Metabolism BioPharmaceuticals R and D AstraZeneca Gaithersburg MD USA

Faculty of Medicine in Hradec Králové Charles University Hradec Králové Czech Republic

Faculty of Medicine University of Brasília Brasília Brazil

Flinders University Flinders Medical Centre Adelaide South Australia Australia

Heart and Vascular Centre Department of Cardiology Faculty of Medicine Semmelweis University Budapest Hungary

IdiPaz Research Institute and Hospital Universitario La Paz Madrid Spain

IDOR D'Or Institute for Research and Education Brasília Brazil

Johns Hopkins University Baltimore MD USA

Kyoto University Hospital Kyoto Japan

Massachusetts General Hospital Boston MA USA

Section of Cardiovascular Medicine Yale School of Medicine New Haven CT USA

TIMI Study Group Division of Cardiovascular Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA USA

Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne UK

VA Connecticut Healthcare System West Haven CT USA

Zobrazit více v PubMed

Maiolino, G. et al. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators Inflamm. 2013, 714653 (2013). PubMed DOI PMC

Kataoka, H. et al. Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation 99, 3110–3117 (1999). PubMed DOI

Sawamura, T. et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 386, 73–77 (1997). PubMed DOI

Kataoka, K. et al. LOX-1 pathway affects the extent of myocardial ischemia-reperfusion injury. Biochem. Biophys. Res. Commun. 300, 656–660 (2003). PubMed DOI

Pothineni, N. V. K. et al. LOX-1 in atherosclerosis and myocardial ischemia: biology, genetics, and modulation. J. Am. Coll. Cardiol. 69, 2759–2768 (2017). PubMed DOI

Kataoka, H. et al. Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arter. Thromb. Vasc. Biol. 21, 955–960 (2001). DOI

Akhmedov, A. et al. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): a crucial driver of atherosclerotic cardiovascular disease. Eur. Heart J. 42, 1797–1807 (2021). PubMed DOI

Villa, M. et al. Pro-fibrotic effect of oxidized LDL in cardiac myofibroblasts. Biochem. Biophys. Res. Commun. 524, 696–701 (2020). PubMed DOI

Lu, J. et al. LOX-1 abrogation reduces cardiac hypertrophy and collagen accumulation following chronic ischemia in the mouse. Gene Ther. 19, 522–531 (2012). PubMed DOI

Hu, C. et al. Modulation of angiotensin II-mediated hypertension and cardiac remodeling by lectin-like oxidized low-density lipoprotein receptor-1 deletion. Hypertension 52, 556–562 (2008). PubMed DOI

Mehta, J. L. et al. Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet. Circ. Res. 100, 1634–1642 (2007). PubMed DOI

Yokoyama, C. et al. Deletion of LOX-1 protects against heart failure induced by doxorubicin. PLoS ONE 11, e0154994 (2016). PubMed DOI PMC

Vavere, A. L. et al. Lectin-like oxidized low-density lipoprotein receptor 1 inhibition in type 2 diabetes: phase 1 results. J. Am. Heart Assoc. 12, e027540 (2023). PubMed DOI PMC

Inoue, K., Arai, Y., Kurihara, H., Kita, T. & Sawamura, T. Overexpression of lectin-like oxidized low-density lipoprotein receptor-1 induces intramyocardial vasculopathy in apolipoprotein E-null mice. Circ. Res. 97, 176–184 (2005). PubMed DOI

Mango, R. et al. In vivo and in vitro studies support that a new splicing isoform of OLR1 gene is protective against acute myocardial infarction. Circ. Res. 97, 152–158 (2005). PubMed DOI

Mango, R. et al. Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction. J. Med Genet 40, 933–936 (2003). PubMed DOI PMC

Tatsuguchi, M. et al. Oxidized LDL receptor gene (OLR1) is associated with the risk of myocardial infarction. Biochem. Biophys. Res. Commun. 303, 247–250 (2003). PubMed DOI

Schnapp, G. et al. A small-molecule inhibitor of lectin-like oxidized LDL receptor-1 acts by stabilizing an inactive receptor tetramer state. Commun. Chem. 3, 75 (2020). PubMed DOI PMC

Murase, T. et al. Identification of soluble forms of lectin-like oxidized LDL receptor-1. Arter. Thromb. Vasc. Biol. 20, 715–720 (2000). DOI

Kobayashi, N. et al. Soluble lectin-like oxidized LDL receptor-1 (sLOX-1) as a valuable diagnostic marker for rupture of thin-cap fibroatheroma: verification by optical coherence tomography. Int. J. Cardiol. 168, 3217–3223 (2013). PubMed DOI

West, N. E. J. et al. Percutaneous sampling of local biomolecule gradients across coronary artery atherosclerotic plaques. JACC Basic Transl. Sci. 2, 646–654 (2017). PubMed DOI PMC

Kraler, S. et al. Soluble lectin-like oxidized low-density lipoprotein receptor-1 predicts premature death in acute coronary syndromes. Eur. Heart J. 43, 1849–1860 (2022). PubMed DOI

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. 9, e013803 (2020). PubMed DOI PMC

Dey, A. K. et al. Association between soluble lectinlike oxidized low-density lipoprotein receptor-1 and coronary artery disease in psoriasis. JAMA Dermatol. 156, 151–157 (2020). PubMed DOI

Lo, J. et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV 2, e52–e63 (2015). PubMed DOI PMC

Bonaca, M. P. et al. Randomized, placebo-controlled phase 2b study to evaluate the safety and efficacy of recombinant human lecithin cholesterol acyltransferase in acute ST-segment-elevation myocardial infarction: results of REAL-TIMI 63B. Circulation 146, 907–916 (2022). PubMed DOI

Lu, M. T. et al. Effects of pitavastatin on coronary artery disease and inflammatory biomarkers in HIV: mechanistic substudy of the REPRIEVE randomized clinical trial. JAMA Cardiol. 9, 323–334 (2024). PubMed DOI PMC

Nieman, K. et al. Standards for quantitative assessments by coronary computed tomography angiography (CCTA): an expert consensus document of the Society of Cardiovascular Computed Tomography (SCCT). J. Cardiovasc. Comput. Tomogr. 18, 429–443 (2024). PubMed DOI