Premature Acute Myocardial Infarction Treated with Invasive Revascularization: Comparing STEMI to NSTEMI in a Population-Based Study of Young Patients.

BACKGROUND: Acute myocardial infarction (AMI) usually presents in older populations, where there are established demographic and outcome differences between ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). No similar comparisons for young AMI exist. METHODS: We compared all index NSTEMI and STEMI hospitalizations in the young (18-45 years) requiring revascularization in Alberta, Canada. Outcomes were survival to discharge, and a composite of heart failure hospitalization, cardiac arrest hospitalization, and all-cause mortality at 1- and 5-years. RESULTS: There were 1679 patients included with an index AMI requiring revascularization (655 (39.0%) NSTEMI and 1024 (61.0%) STEMI). The population was disproportionately male (86%), particularly in STEMI (87.3%). Marked dyslipidemia (35%) and active smoking (42%) were common, with similar rates between groups. Percutaneous coronary intervention was used in 98.7% of STEMI and 91.5% of NSTEMI patients (P<0.001), with the remainder undergoing surgical revascularization. In-hospital mortality during index AMI was higher STEMI compared to NSTEMI patients (1.7% vs 0%, P<0.001). The rates of the composite outcome were similar between groups at 1- and 5-years of follow-up in patients who survived to index hospital discharge. After adjusting for sex, age, heart failure and/or cardiac arrest at index AMI, outcomes remained similar between groups at 1- and 5-years. CONCLUSIONS: In young patients with AMI, STEMI was a disproportionately male phenomenon and associated with higher mortality at index hospitalization. One-year and 5-year outcomes were similar between STEMI and NSTEMI in those discharged alive at index AMI. Smoking and dyslipidemia appear to be major risk factors in the young.

Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice.

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-ß (Aß) deposition. Mice expressing CD33M have increased Aß levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

A versatile soluble siglec scaffold for sensitive and quantitative detection of glycan ligands.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. The connections between Siglecs and human disease motivate improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands are systematically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs are clarified. For CD33 (Siglec-3), we demonstrate that it recognizes both α2-3 and α2-6 sialosides in solution and on cells, which has implications for its link to Alzheimer's disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.