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

Abstract

Background: The noncoding antisense transcript for β-secretase-1 (BACE1-AS) is a long noncoding RNA with a pivotal role in the regulation of amyloid-β (Aβ). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD).

Methods: Expression of BACE1-AS and its target, β-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 Aβ1-40 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).

Conclusion: BACE1-AS is associated with the incidence and severity of ASCVD.

Fig. 1

Estimated marginal means of: ( A ) Aβ1–40 across BACE1 -AS tertiles, ( B ) BACE1 expression across BACE1-AS tertiles. Number of participants in each BACE1-AS tertile: 1st tertile N  = 144, 2nd tertile N  = 146, 3rd tertile N  = 144. p -Values were derived from linear regression analysis. Relative BACE1-AS, BACE1 expression, and plasma Aβ1-40 (pg/mL) were transformed to logarithmic scale prior to analysis. ; Aβ1–40, amyloid β 1–40; BACE1 , β secretase-1; BACE1-AS , β secretase antisense RNA.

Fig. 2

Cumulative incidence of major adverse cardiovascular events (cardiovascular death, acute myocardial infarction, and revascularization procedure) in high/very high CVD risk patients (total N  = 237) according to BACE1-AS tertiles, initially defined in the whole population. The number of patients at risk is depicted beneath the graph. BACE1-AS tertiles were derived from the total population. p  < 0.001, by log-rank test of equality. HR = 2.42 per ascending tertile (95% CI: 1.39–4.22), p  = 0.002, by Cox regression analysis. HR = 1.86 per ascending tertile (95% CI: 1.011–3.43), p  = 0.046, after multivariable adjustment for age, gender, presence of coronary artery disease, diabetes mellitus, and hypertension. BACE1-AS , β secretase antisense RNA; CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio.