👤 Michael J Blaha

The utility of coronary artery calcium (CAC) scoring in individuals with elevated lipoprotein(a) [Lp(a)] for atherosclerotic cardiovascular disease (ASCVD) risk assessment is currently unclear given the propensity of Lp(a) toward noncalcified plaque. The authors aimed to evaluate the interaction between elevated Lp(a) (>50 mg/dL) and CAC score, and the association of Lp(a) with ASCVD risk across strata of CAC. A pooled cohort of participants without known ASCVD from 4 U.S.-based prospective cohort studies with baseline Lp(a) and CAC measurements was used. The association between elevated Lp(a) across CAC strata and incident ASCVD (myocardial infarction, stroke, coronary revascularization) was evaluated in multivariable Cox regression models. The study included 11,319 participants (mean age 56 years, 54% women) with 1,569 incident ASCVD events over 14.8 year mean follow-up. Lp(a) >50 mg/dL (HR: 1.24; 95% CI: 1.09-1.41) and CAC >0 (HR: 2.44; 95% CI: 2.14-2.77) were independently associated with ASCVD risk (P interaction = 0.80). Among individuals with CAC = 0, ASCVD incidence rates were low overall, but higher with Lp(a) >50 mg/dL vs ≤50 mg/dL (4.9 vs 3.8/1,000 person-years, HR: 1.28; 95% CI: 1.01-1.60). Among those with CAC >0, increased risk was again noted with elevated Lp(a) (21.2 vs 18.2/1,000 person-years, HR: 3.03; 95% CI: 2.52-3.64). Similar results were observed when examining further CAC strata with the greatest risk noted with both CAC ≥300 and Lp(a) >50 mg/dL (HR: 6.12; 95% CI: 4.80-7.81). Consistent results were noted by age and sex with greater absolute risk in general among individuals >50 years of age and men. Elevated Lp(a) is associated with higher relative risk across CAC strata, including CAC of 0. Among individuals with CAC of 0, absolute event rates remain low even when Lp(a) is elevated. CAC scoring remains a powerful tool for risk assessment among individuals with elevated Lp(a). Show less

Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a). Show less

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis. HK2 binds and sequesters glycogen synthase kinase 3 (GSK3) and acts as a scaffold forming a ternary complex with the regulatory subunit of protein kinase A (PRKAR1a) and GSK3β to facilitate GSK3β phosphorylation and inhibition by PKA. Thus, HK2 functions as an A-kinase anchoring protein (AKAP). Phosphorylation by GSK3β targets proteins for degradation. Consistently, HK2 increases the level and stability of GSK3 targets, MCL1, NRF2, and particularly SNAIL. In addition to GSK3 inhibition, HK2 kinase activity mediates SNAIL glycosylation, which prohibits its phosphorylation by GSK3. Finally, in mouse models of breast cancer metastasis, HK2 deficiency decreases SNAIL protein levels and inhibits SNAIL-mediated epithelial mesenchymal transition and metastasis. Show less