👤 Regina Grün

Elevated Lipoprotein(a) Lp(a) levels are associated with coronary atherosclerosis as detected by cardiac computed tomography angiography (CCTA). However, quantitative data including coronary plaque volumes and characteristics are scarce. The current study evaluated the sex-specific correlations between (Lp(a)) levels and the extent and composition of coronary stenosis and plaques. 1,946 patients undergoing CCTA (third-generation dual-source scanner) for suspected coronary artery disease were included whose Lp(a) levels were available. Lp(a) values ≥ 125 nmol/L were classified as high. High Lp(a) levels were observed in 336 patients, who had greater maximum degree of stenosis (49.5 ± 26.4% vs. 43.5 ± 27.6%, P = 0.002), mainly as a result of the pronounced difference in males (53.8 ± 26.0% vs. 46.2 ± 26.8%, P = 0.001). A strong correlation between higher Lp(a) values and high-risk plaque features was noted in the overall cohort (odds ratio [OR]: 1.645; 95% confidence interval [CI]: 1.011 to 2.593; P = 0.037), independent of age and LDL-cholesterol values. In males, high Lp(a) levels were associated with greater total plaque volumes (118.1 [IQR 18.3-284.4] vs. 83.2 [IQR 11.8-226.3] mm Our study identifies novel sex-specific correlations between Lp(a) levels and coronary plaque characteristics. High Lp(a) levels in men seems to be associated with increased fibrotic plaque volumes and may contribute to greater total plaque burden and high-risk plaque features. Show less

Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the β-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants. Show less