ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance.

Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased CVD risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDL receptor-mediated and LDL receptor-related protein 1-mediated hepatic TRL clearance and that apoC-III-enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe-/-Ndst1f/fAlb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe-/-Ndst1f/fAlb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe-/-Ndst1f/fAlb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue in the fed state. Finally, clinical data confirmed that ASO-mediated lowering of APOC-III via volanesorsen can reduce plasma TG levels independent of the APOE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that, in the absence of functional apoE, apoC-III inhibits tissue LPL activity.

Radiographic comparison of L5-S1 lateral anterior lumbar interbody fusion cage subsidence and displacement by fixation strategy: anterior plate versus integrated screws.

OBJECTIVE: The aim of this study was to radiographically compare cage subsidence and displacement between L5-S1 lateral anterior lumbar interbody fusion (ALIF) cages secured with an anterior buttress plate and cages secured with integrated screws. METHODS: Consecutive patients who underwent L5-S1 lateral ALIF with supplemental posterior fixation by a single surgeon from June 2016 to January 2021 were reviewed. Radiographs were analyzed and compared between the two groups based on the type of fixation used to secure the L5-S1 lateral ALIF cage: 1) anterior buttress plate or 2) integrated screws. The following measurements at L5-S1 were analyzed on radiographs obtained preoperatively, before discharge, and at latest follow-up: 1) anterior disc height, 2) posterior disc height, and 3) segmental lordosis. Cage subsidence and anterior cage displacement were determined radiographically. RESULTS: One hundred thirty-nine patients (mean age 60.0 ± 14.3 years) were included for analysis. Sixty-eight patients were treated with an anterior buttress plate (mean follow-up 12 ± 5 months), and 71 were treated with integrated screws (mean follow-up 9 ± 3 months). Mean age, sex distribution, preoperative L5-S1 lordosis, preoperative L5-S1 anterior disc height, and preoperative L5-S1 posterior disc height were statistically similar between the two groups. After surgery, the segmental L5-S1 lordosis and L5-S1 anterior disc heights significantly improved for both groups, and each respective measurement was similar between the groups at final follow-up. Posterior disc heights significantly increased after surgery with integrated screws but not with the anterior buttress plate. As such, posterior disc heights were significantly greater at final follow-up for integrated screws. Compared with patients who received integrated screws, significantly more patients who received the anterior buttress plate had cage subsidence cranially through the L5 endplate (20.6% vs 2.8%, p < 0.01), cage subsidence caudally through the S1 endplate (27.9% vs 0%, p < 0.01), and anterior cage displacement (22.1% vs 0%, p < 0.01). CONCLUSIONS: In this radiographic analysis of 139 patients who underwent lateral L5-S1 ALIF supplemented by posterior fixation, L5-S1 cages secured with an anterior buttress plate demonstrated significantly higher rates of cage subsidence and anterior cage displacement compared with cages secured with integrated screws. While the more durable stability afforded by cages secured with integrated screws suggests that they may be a more viable fixation strategy for L5-S1 lateral ALIFs, there are multiple factors that can contribute to cage subsidence, and, thus, definitive presumption cannot be made that the findings of this study are directly related to the buttress plate.

Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.

Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.