Non-Linear Relationship between Anti-Apolipoprotein A-1 IgGs and Cardiovascular Outcomes in Patients with Acute Coronary Syndromes

Abstract

Autoantibodies against apolipoprotein A-I (anti-apoA-I IgGs) are prevalent in atherosclerosis-related conditions. It remains elusive whether they improve the prognostic accuracy of the Global Registry of Acute Coronary Events (GRACE) score 2.0 (GS) in acute coronary syndromes (ACS). In this prospective multicenter registry, 1713 ACS patients were included and followed for 1 year. The primary endpoint (major adverse cardiovascular events (MACE)) was defined as the composite of myocardial infarction, stroke (including transient ischemic attack), or cardiovascular (CV) death with individual events independently adjudicated. Plasma levels of anti-apoA-I IgGs upon study inclusion were assessed using ELISA. The association between anti-apoA-I IgGs and incident MACE was assessed using Cox models with splines and C-statistics. One-year MACE incidence was 8.4% (144/1713). Anti-apoA-I IgG levels were associated with MACE with a non-linear relationship (p = 0.01), which remained unchanged after adjusting for the GS (p = 0.04). The hazard increased progressively across the two first anti-apoA-I IgG quartiles before decreasing thereafter. Anti-apoA-I IgGs marginally improved the prognostic accuracy of the GS (c-statistics increased from 0.68 to 0.70). In this multicenter study, anti-apoA-I IgGs were predictive of incident MACE in ACS independently of the GS but in a nonlinear manner. The practical implications of these findings remain to be defined.

Anti-ApoA-1 IgGs in Familial Hypercholesterolemia Display Paradoxical Associations with Lipid Profile and Promote Foam Cell Formation

“…Among autoantibodies of interest in CVD, the interest in antibodies against apolipoprotein A-1 (anti-ApoA-1 IgG) appears to be gaining momentum. Indeed, three recent studies derived from a large multicenter general population cohort demonstrated that anti-ApoA-1 IgGs were an independent cardiovascular (CV) risk factor predictive of poor prognosis [3][4][5] similarly to what had been reported previously and more recently in high CV risk populations [6][7][8][9][10][11]. In parallel, translational studies pointed to these autoantibodies as mediators of atherogenesis, promoting atherosclerosis, myocardial necrosis, and mice death through toll-like receptors (TLR) 2,4 and CD14 signaling [12][13][14].…”

Prognostic and therapeutic considerations of antibodies against c‐ter apolipoprotein A‐1 in the general population

“…Multivariate HRs were calculated after adjusting for age, gender, hypertension, diabetes, smoking, BMI, eGFR, HDL and LDL cholesterol, baseline CVD, and ADs. Humoral autoimmunity against apoA1 being known to be relevant for CVD, 2,3,5,8,10,11 sensitivity analyses were performed in primary and secondary prevention subgroups. Secondary prevention individuals were defined by the anamnestic presence of any CAD, any stroke or peripheral artery disease.…”

“…During the last decade, evidence has accumulated that autoantibodies against high‐density lipoproteins (HDLs) and their components impact multiple pro‐atherogenic processes, facilitating atherogenesis and the occurrence of cardiovascular (CV) diseases 1 . Autoantibodies of the IgG subclass against apolipoprotein A1 (anti‐apoA1 IgG), the major apolipoprotein of HDL, have been shown to be an independent CV risk factor in the general population, as well as predictors of poor CV outcomes and overall mortality in most populations reported so far 2–11 . Translational investigations showed that anti‐apoA1 IgGs efficiently promote sterile inflammation, facilitate foam cell formation in vitro, and enhance the development of atherosclerosis and atherothrombosis in mice through specific innate immune receptors complexes and related signalling pathways 12–18 .…”

SARS-CoV2- infection as a trigger of humoral response against apolipoprotein A-1

“…TLR2 engagement and subsequent activation have been shown to be required for autoantibodies against apoA-1 (anti-apoA-1 IgG) to mediate their pro-atherogenic effects (17)(18)(19)(20). Because anti-apoA-1 IgGs were shown to represent an independent cardiovascular (CV) risk factor associated with poor prognosis (21)(22)(23)(24)(25), to be elevated after viral infections (26,27), and to be preferentially oriented against the c-ter part of apoA-1 (28,29), we hypothesized that SARS-CoV-2 infection could elicit an anti-apoA-1 IgG response with substantial overlap with anti-SARS-CoV-2 IgG serology.…”