265Amyloid beta 1-40 and its upstream regulatory pathway BACE1-AS long noncoding RNA/BACE1 are associated with presence and severity of human atherosclerotic disease

Background Amyloid-beta (1-40) (Aβ1–40), a proinflammatory and pro-atherosclerotic peptide, is associated with accelerated atherosclerosis and major adverse cardiac events. Abeta1–40 production is mainly dependent on the cleavage of amyloid precursor protein by β-amyloid cleaving enzyme-1 (BACE1), known as beta-secretase. BACE1 antisense (BACE1-AS) is a long noncoding RNA that enhances BACE1 stability. Objectives To evaluate the clinical value of plasma amyloid-beta levels and its upstream regulatory pathway BACE1/BACE1-AS in patients with subclinical and established atherosclerotic cardiovascular disease. Methods Plasma levels of Aβ40 were measured in 642 consecutively recruited patients with and without clinically overt coronary artery disease (CAD). BACE1-AS lncRNA and BACE1 mRNA expression were measured in peripheral blood mononuclear cells derived from 214 study participants. Intima-media thickness and atheromatous plaques by ultrasonography, markers of arterial wave reflections and pulse wave velocity were used as surrogate markers of subclinical CVD. Cardiovascular risk factors (CVRFs), including impaired glomerular filtration rate (<60 ml/min), smoking, hypertension, hyperlipidemia, diabetes, obesity and increased hsCRP (>2 mg/l) were assessed as a measure of CVRF burden. Results Both in non-CAD (n=369) and CAD (n=273) patients, Aβ1–40 was associated with age, aortic and peripheral systolic and pulse pressure, and low GFR (p<0.05 for all). In non-CAD subjects Aβ1–40 also correlated with diabetes and low HDL. Importantly, Aβ1–40 was associated with the presence of any plaque in subjects without CAD (p=0.035) and with increased number of diseased coronary arteries (p=0.022) independently of age, gender and CVRFs. Aβ1–40 plasma levels were increased in the highest tertile of BACE1 and BACE1AS (p<0.05) while their expression levels were highly intercorrelated (r=0.825, P<0.001). BACE1 and BACE1-AS levels progressively increased across the 3 groups of non-CAD (n=145), stable CAD (n=43) and acute myocardial infarction (n=26) patients (p for trend<0.001). Among non-CAD subjects, both BACE1 and BACE1-AS were increased in individuals with >2 CVRFs. Among CAD patients, BACE1-AS was associated with decreased LVEF (<50%) (adjusted OR=1.92 per 1-SD increase, p=0.047) while BACE1 in the highest tertile was associated with 5-fold higher odds for coronary multi-vessel disease (p=0.004) after adjustment for age, gender and CVRFs. Conclusions Circulating Aβ1–40 and increased expression of its upstream regulators BACE1/BACE1-AS are intercorrelated and associated with the presence and severity of subclinical and clinically overt atherosclerosis. These findings suggest that BACE1-AS/BACE1-mediated increased availability of Aβ1–40 may play a pivotal role in its adverse cardiovascular effects.