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Introduction: Almost 30% of US adults have elevated low-density lipid cholesterol (LDL-C) increasing their risk of atherosclerotic cardiovascular disease (ASCVD). The 2018 American College of Cardiology/American Heart Association Multisociety Cholesterol Guideline recommends maximally tolerated statin for those at increased ASCVD risk and add-on therapies (ezetimibe and PCSK9 inhibitors) for those at very high risk with LDL-C>=70 mg/dl, but prescription fill trends are unknown. Method(s): Using the IQVIA Total Patient Tracker database (covering ~93% of outpatient retail prescriptions in the US) from Q1 2017-Q1 2022, we determined counts of patients who filled low-, moderate-, or high-intensity statins alone and with ezetimibe or PCSK9 inhibitors. Overall percent change and joinpoint regression were used to assess trends. Result(s): From Q1 2017-Q1 2022, patients filling any statin intensity increased 25% with the greatest increase in high-intensity statins (64.1%). Concurrent fills of high-intensity statin and ezetimibe rose 210%, with an increase in slope by Q2 2019 for all statin intensities (p<0.001, Figure A). Patients filling a PCSK9 inhibitor and all statin intensities increased over the study period (2124% for high-intensity), with increases in slope in Q2 2019 and continued increase in fills but less sharp rise in Q1 2020 (p<0.001, Figure B). Conclusion(s): Increasing prescription fills of high-intensity statins and add-on ezetimibe and PCSK9 inhibitors indicate uptake of guideline-concordant lipid-lowering therapies for cardiovascular disease prevention. There is need for continuity of PCSK9 inhibitor therapy which may have been disrupted during COVID-19. (Figure Presented).
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Background: Severe infection with SARS-CoV-2 induces systemic autoreactive antibodies with specificity to Type I IFN, phospholipids, nuclear or tissue specific targets. The wide breadth of targets suggests a system-wide defect in B cell tolerance during viral infection and that the source of autoreactive antibodies is likely a heterogenous subset of B cells. BND cells are mature naïve B cells that do not express IgM but do express IgD and are enriched in autoreactive specificities. BND cells are held in an anergic state in healthy humans as a mechanism of peripheral tolerance, although in vitro evidence suggests anergy can be broken with strong inflammation. We hypothesized that robust inflammation associated with viral infection from SARS-CoV2 may relax peripheral tolerance and promote breakage of BND cell anergy. Methods: Plasma and PBMCs were collected from healthy controls (N=10), subjects immunized with Pfizer BNT162b2-mRNA/Moderna mRNA-1273 (N=10), subjects with mild (N=11) or severe SARS-CoV-2 infection (N=14). BND cells were examined ex vivo for markers of activation by flow cytometry. Phosphorylation of signaling proteins downstream of the BCR were measured in vitro with or without BCR crosslinking. Inflammatory cytokines were measured in plasma by multiplex. For statistical analysis, unpaired t test between populations or paired t test between unstimulated and BCR stimulated conditions were performed. Results: BND cells from severe SARS-CoV-2 infection have lower expression of CD21, associated with loss of anergy, higher expression of activation markers CD68 and CD86 with lower expression of inhibitory receptors CD22 and CD72 when compared to BND cells from other subjects, suggesting a phenotypical breach of anergy. Upon BCR crosslinking, BND cells have higher levels of downstream signaling components of the BCR (pPLCγ2, pBlnk, and pSyk) when compared to healthy controls and immunized subjects, suggesting a functional breach in anergy with infection. Examination of plasma from severe SARS-CoV-2 infection showed higher levels of inflammatory cytokines (IFNγ, TNFα, IL-6 and CRP) where TNFα and CRP correlated with enhanced BCR signaling in BND cells. Conclusion: We demonstrate that SARS-CoV-2 viral infection relaxes peripheral tolerance of BND cells, likely through strong systemic inflammation produced during infection. These autoreactive cells overcome anergy and become activated with increased BCR signaling. Thus BND cells could be a source of autoreactive antibodies during viral infection.