Citations

Background: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation. Methods: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry–based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy. Results: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3 + T cells in the atherosclerotic lesions suggested a T-cell–related effect of homoarginine supplementation, which was mainly attributed to CD4 + T cells. Macrophages, dendritic cells, and B cells were not affected. CD4 + T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects. Conclusions: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.

OBJECTIVEThe authors assessed the prognostic significance of various clinical and radiographic characteristics, including C1–C2 facet malalignment, in terms of surgical outcomes after foramen magnum decompression of adult Chiari malformation type I.METHODSThe electronic medical records of 273 symptomatic patients with Chiari malformation type I who were treated with foramen magnum decompression, C1 laminectomy, and duraplasty at Mayo Clinic were retrospectively reviewed. Preoperative and postoperative Neurological Scoring System scores were compared using the Friedman test. Bivariate analysis was conducted to identify the preoperative variables that correlated with the patient Chicago Chiari Outcome Scale (CCOS) scores. Multiple linear regression analysis was subsequently performed using the variables with p < 0.05 on the bivariate analysis to check for independent associations with the outcome measures. Statistical software SPSS version 25.0 was used for the data analysis. Significance was defined as p < 0.05 for all analyses.RESULTSFifty-two adult patients with preoperative clinical and radiological data and a minimum follow-up of 12 months were included. Motor deficits, syrinx, and C1–C2 facet malalignment were found to have significant negative associations with the CCOS score at the 1- to 3-month follow-up (p < 0.05), while at the 9- to 12-month follow-up only swallowing function and C1–C2 facet malalignment were significantly associated with the CCOS score (p < 0.05). Multivariate analysis showed that syrinx presence and C1–C2 facet malalignment were independently associated with the CCOS score at the 1- to 3-month follow-up. Swallowing function and C1–C2 facet malalignment were found to be independently associated with the CCOS score at the 9- to 12-month follow-up.CONCLUSIONSThe observed results in this pilot study suggest a significant negative correlation between C1–C2 facet malalignment and clinical outcomes evaluated by the CCOS score at 1–3 months and 9–12 months postoperatively. Prospective studies are needed to further validate the prognostic value of C1–C2 facet malalignment and the potential role of atlantoaxial fixation as part of the treatment.