Vascular calcification (VC) is an urgent worldwide health issue with no available medical treatment. It is an active cell-driven process by osteogenic differentiation of vascular cells with complex mechanisms. The AMP-activated protein kinase (AMPK) serves as the master sensor of cellular energy status. Accumulating evidence reveals the vital role of AMPK in VC progression. AMPK is involved in VC in various ways, including inhibiting runt-related transcription factor 2 signaling pathways, triggering autophagy, attenuating endoplasmic reticulum stress and dynamic-related protein 1-mediated mitochondrial fission, and activating endothelial nitric oxide synthase. AMPK activators, like metformin, are associated with reduced calcification deposits in certain groups of patients, indicating that AMPK is a potential therapeutic target for VC.
Background: Metformin is the first-line antidiabetic medication for type 2 diabetes mellitus (T2DM). However, the association between metformin and outcomes in T2DM patients with heart failure with preserved ejection fraction (HFpEF) is still unknown. We aimed to explore the association between metformin and adverse outcome in T2DM patients with HFpEF.Methods: A total of 372 T2DM patients with HFpEF hospitalized from January 1, 2013, to December 31, 2017, were included in this retrospective cohort study. There were 113 and 259 subjects in metformin and non-metformin group, respectively. Subjects were followed up for all-cause mortality, cardiovascular death, all-cause hospitalization, and heart failure hospitalization.Results: The median follow-up period was 47 months. Eleven patients (2.49% per patient-year) in the metformin group and 56 patients (5.52% per patient-year) in the non-metformin group deceased during follow-up (P = 0.031). However, a multivariable Cox regression failed to show that metformin was an independent factor of all-cause mortality [HR (95% CI) = 0.682 (0.346–1.345); P = 0.269]. A subgroup analysis revealed a significant association between metformin and all-cause mortality in patients with a higher hemoglobin A1c (HbA1c) level (HbA1c ≥7%) [HR (95% CI) = 0.339 (0.117–0.997); P = 0.045]. The 4-year estimated number needed to treat (NNT) with metformin compared with non-metformin for all-cause mortality was 12 in all populations and 8 in the HbA1c ≥7% subgroup.Conclusions: Metformin was not independently associated with clinical outcomes in patients with T2DM and HFpEF, but was associated with lower all-cause mortality in the subgroup of patients with poor glycemic control. Prospective, randomized controlled trials are needed to further verify these findings.
Background: Abdominal aortic aneurysm (AAA) is recently recognized as an autoimmune-induced vascular disease. Nonetheless, the inflammatory cellular heterogeneity and specialty within the aortic wall have not been fully identified. Methods: Infrarenal abdominal aortas of WT mice were perfused with PBS or elastase to simulate sham or AAA models. The aortas were harvested 14 days after surgery and digested for single-cell preparation. The cell pellet was mixed with CD45 microbeads, and proceeded with magnetic separation to isolate CD45 positive immune cell suspension. The cell suspension was loaded into Chromium microfluidic chips with 3’ chemistry and barcoded with 10х Chromium Controller (10X Genomics). All downstream single-cell analyses were performed using the CellRanger, Seurat, or clusterProliler R package. Results: Based on the filtered gene expression matrix, 18 clusters were identified in the final datasets. Enrichment analysis was performed to finger out the specific biological behaviors, such as inflammatory cytokine secretions and promotion of cell proliferation, in each clusters of immune cells. According to the highly expressed cell markers and biological behaviors, we divided each clusters of immune cells into macrophages, dendritic cells (DCs), T or B lymphocytes. It was shown in the t-SNE plot that the cellular quantity of CD45 positive immune cells, especially macrophages and DCs, were prominently altered in the AAA group. The refined subtypes of each kinds of inflammatory cells were distinguished and identified by limiting essential cell markers and increase dimensionality resolution. The specific marker-based analysis showed that the cell count difference of resident macrophages and monocyte-derived DCs (moDCs) are most noticeable between the AAA and the sham group, which might suggest these cells have eventful influence in aneurysm development. Conclusions: The integrated data exhibited the distinctive heterogeneity of CD45 positive immune cells within elastase-induced AAA samples. Some of these cells, such as resident macrophages and moDCs, may play an essential role through several pathways in the pathogenesis of AAA formation according to our scRNA-sequencing result.
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