Income is the standard indicator of low-end households’ living standards. With income as the measure, the comparative evidence suggests that economic growth has tended to be the principal driver of improved living standards, though government social programs have been the chief conduit through which growth trickles down. Material deprivation may be a better indicator. With deprivation as the measure, the available evidence suggests an even stronger and more direct impact of social policy.
Background Aortic valve stenosis (AVS) is the most common valve disease worldwide. Thought to be a purely degenerative disease, it is now clear that shear stress/endothelial dysfunction, lipid deposition and inflammation lead to calcification and stenosis of the valve. There is evidence, that extracellular vesicles (EVs) are actively involved in calcification processes. Practically all cells, including endothelial cells, can generate EVs, which can be shed into the blood stream and into the interstitial space. EVs contain lipids, proteins and nucleic acids, including noncoding RNAs (ncRNAs). EVs can be taken up by acceptor cells and their cargo, especially the ncRNA content, can change the phenotype of these cells. NcRNAs have been shown to have protective and damaging properties in AVS, which can lead to disease progression. EVs are actively involved in atherosclerosis and vascular calcification, but their role during AVS formation remains largely unknown. Purpose We hypothesize, that EV-derived ncRNAs play a crucial role during calcification of the aortic valve through regulation of endothelial to mesenchymal transition (EndMT) and calcification of valvular interstitial cells. Methods and results In initial screening experiments, we investigated ncRNA (micro RNA, miRNA and long noncoding RNA, lncRNA) content in aortic valve tissue from explanted human aortic valves from patients undergoing surgical aortic valve replacement. There is a differential expression of miRNAs and lncRNAs in aortic valve tissue from patients with AVS and patients without AVS. We could also show a differential packaging of ncRNAs into EVs generated from patient aortic valve tissues. Furthermore, ncRNA expression in aortic valve tissue is altered in a “wire-injury” mouse model of AVS. We can demonstrate in vitro that EVs and their content can be transferred from valvular endothelial cells (VECs) to valvular interstitial cells (VICs) and vice versa. Additionally, we have established an isolation method of VECs and VICs from human samples. To identify ncRNAs involved in EndMT, we are investigating the effect of laminar and pulsatile flow on the expression of ncRNAs in vitro. We can demonstrate that different flow patterns lead to a vast change in ncRNA expression in primary VECs. Downstream effects of identified ncRNAs are currently under investigation in our in vitro calcification and EndMT models. Transfection of VICs with miRNA mimics and inhibitors and lentiviral transduction of our identified targets lead to an altered calcification potential of valve cells. Conclusion The analysis of the cell type specific expression of ncRNAs and the intercellular communication via EVs will greatly help our understanding of the pathomechanisms leading to valvular calcification. Pathway analysis will generate new targets that could be used to develop therapeutics to ameliorate disease progression. EV-based miRNA mimics and inhibitors could be used to treat valvular calcification. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft, TRR259; Else-Kröner-Fresenius
Objective Coronary artery bypass grafting (CABG) is a surgical procedure routinely performed using extracorporeal circulation (ECC). This on‐pump CABG is known to be associated with severe postoperative organ failure including cardiac dysfunction and low cardiac output syndrome. Mechanisms inducing cardiac dysfunction are complex but may include on‐pump CABG induced inflammation due to exposure of the blood to the bypass circuit, potentially increasing serum concentrations of inflammatory mediators. High‐mobility group box 1 (HMGB1) functions as an inflammatory mediator and has been shown to induce cardiovascular dysfunction in sepsis and impair cardiomyocyte contractility in experimental models. However, the impact of HMGB1 on on‐pump CABG induced myocardial dysfunction is not known. Therefore, we tested the hypothesis that on‐pump CABG associated increases in serum concentrations of inflammatory mediators induce cardiomyocyte dysfunction in vitro and investigated potential mechanism including the role of the HMGB1‐RAGE (receptor for advanced glycation end products) axis. Approach After institutional revenue board approval, informed consent, and IACUC approval, serum samples (n = 18) were collected from CABG patients pre, 1, 6, and 24 h after aortic de‐clamping. TNFa, IL‐1b, IL‐6, HMGB1, and sRAGE serum concentrations were analyzed by ELISA. Primary murine cardiomyocytes were incubated with patient serum and single cell contractility was assessed at frequencies between 0.5 and 10Hz using an optical contractility system (IonOptics LLC, Westwood, MA). Results IL‐6, HMGB1, and sRAGE serum levels were increased after CABG (Figure 1). In preliminary studies we incubated murine cardiomyocytes with human serum collected from healthy volunteers and determined the highest serum concentrations that did not affect cardiomyocyte contractility. Cardiomyocytes were incubate with human serum and serum collected pre‐surgery had no effects on murine cardiomyocyte contractility. However, primary murine cardiomyocytes incubated with serum collected 1h and 6h after aortic de‐clamping showed a significant decrease in % peak shortening. Pre‐incubation with the RAGE antibody FPS‐ZM1 (Cayman, Hamburg, Germany) prevented the serum induced cardiomyocyte dysfunction (Figure 2). Conclusion on‐pump CABG increased protein serum concentrations of inflammatory cytokines including HMGB1. HMGB1 has been shown to cleave and activate RAGE. sRAGE serum levels have been increased after on‐pump CABG. Deactivating RAGE with the high‐affinity inhibitor FPS‐ZM1 prevented serum induced cardiomyocyte dysfunction, suggesting that the HMGB1‐RAGE axis is mediating on‐pump CABG associated low‐cardiac‐output syndrome.
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