Beta-Secretase-1 Antisense RNA Is Associated with Vascular Ageing and Atherosclerotic Cardiovascular Disease

Background and Aims The noncoding antisense transcript for beta-secretase-1 (BACE1-AS) is a long noncoding RNA with a pivotal role in the regulation of amyloid-beta (A beta). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD). Methods Expression of BACE1-AS and its target, beta-secretase 1 (BACE1) mRNA, was measured in peripheral blood mononuclear cells derived from 434 individuals (259 without established ASCVD [non-CVD], 90 with stable coronary artery disease [CAD], and 85 with acute coronary syndrome). Intima-media thickness and atheromatous plaques evaluated by ultrasonography, as well as arterial wave reflections and pulse wave velocity, were measured as markers of subclinical ASCVD. Patients were followed for a median of 52 months for major adverse cardiovascular events (MACE). Results In the cross-sectional arm, BACE1-AS expression correlated with BACE1 expression (r= 0.396, p< 0.001) and marginally with A beta 1-40 levels in plasma (r=0.141, p=0.008). Higher BACE1-AS was associated with higher estimated CVD risk assessed by HeartScore for non-CVD subjects and by European Society of Cardiology clinical criteria for the total population (p < 0.05 for both). BACE1-AS was associated with higher prevalence of CAD (odds ratio [OR] =1.85, 95% confidence interval [CI]: 1.37-2.5), multivessel CAD (OR =1.36, 95% CI: 1.06-1.75), and with higher number of diseased vascular beds (OR =1.31, 95% CI: 1.07-1.61, for multiple diseased vascular beds) after multivariable adjustment for traditional cardiovascular risk factors. In the prospective arm, BACE1-AS was an independent predictor of MACE in high cardiovascular risk patients (adjusted hazard ratio =1.86 per ascending tertile, 95% CI: 1.011-3.43, p= 0.046). Conclusions BACE1-AS is associated with the incidence and severity of ASCVD.