Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.The European Union’s Horizon 2020/Marie Sklodowska-Curie grant agreement No 722609 (INTRICARE);Swedish Heart and Lung FoundationSwedish Research Council (K2009-65X-2233-01-3, K2013- 65X-06816-30-4, 349-2007-8703)Uppdrag Besegra Stroke (P581/ 2011-123)Stockholm County Council (ALF2011-0260, ALF-2011- 0279)Swedish Society for Medical ResearchTore Nilsson’s FoundationMagnus Bergvall’s FoundationKarolinska Institutet FoundationEuropean Commission (722609)Publishe

Postoperative inflammation and insulin resistance in relation to body composition, adiposity and carbohydrate treatment: a randomised controlled study

Background and Aims: The aims of this study were to identify whether differences in distribution of adipose tissue and skeletal muscle in obese and non-obese individuals contribute to the magnitude of the postoperative inflammatory response and insulin resistance, with and without preoperative treatment with carbohydrate drinks. Methods: Thirty-two adults (16 obese/16 non-obese) undergoing elective major open abdominal surgery participated in this 22 factorial, randomised, double-blind, placebo-controlled study. Participants received Nutricia preOp® or placebo (800 ml on the night before surgery/400 ml 2-3 h preoperatively) after stratifying for obesity. Insulin sensitivity was measured using the hyperinsulinaemic-euglycaemic clamp pre- and postoperatively. Vastus lateralis, omental and subcutaneous fat biopsies were taken pre- and postoperatively and analysed after RNA extraction. The primary endpoint was within subject differences in insulin sensitivity. Results: Major abdominal surgery was associated with a 42% reduction in insulin sensitivity from mean(SD) M value of 37.3(11.8) μmol kg-1 fat free mass (FFM) to 21.7(7.4) μmol kg-1 67 FFM, but this was not influenced by obesity or preoperative carbohydrate treatment. Activation of the triggering receptor expressed on myeloid cells (TREM1) pathway was seen in response to surgery in omental fat samples. In postoperative muscle samples, gene expression differences indicated activation of the peroxisome proliferator-activated receptor (PPAR-α)/retinoid X-receptor (RXR-α) pathway in obese but not in non-obese participants. There were no significant changes in gene expression pathways associated with carbohydrate treatment. Conclusion: The reduction in insulin sensitivity associated with major abdominal surgery was confirmed but there were no differences associated with preoperative carbohydrates or obesity

Phosphatidylserine Targets Single-Walled Carbon Nanotubes to Professional Phagocytes In Vitro and In Vivo

Broad applications of single-walled carbon nanotubes (SWCNT) dictate the necessity to better understand their health effects. Poor recognition of non-functionalized SWCNT by phagocytes is prohibitive towards controlling their biological action. We report that SWCNT coating with a phospholipid “eat-me” signal, phosphatidylserine (PS), makes them recognizable in vitro by different phagocytic cells - murine RAW264.7 macrophages, primary monocyte-derived human macrophages, dendritic cells, and rat brain microglia. Macrophage uptake of PS-coated nanotubes was suppressed by the PS-binding protein, Annexin V, and endocytosis inhibitors, and changed the pattern of pro- and anti-inflammatory cytokine secretion. Loading of PS-coated SWCNT with pro-apoptotic cargo (cytochrome c) allowed for the targeted killing of RAW264.7 macrophages. In vivo aspiration of PS-coated SWCNT stimulated their uptake by lung alveolar macrophages in mice. Thus, PS-coating can be utilized for targeted delivery of SWCNT with specified cargoes into professional phagocytes, hence for therapeutic regulation of specific populations of immune-competent cells

Accelerated vascular aging in chronic kidney disease: the potential for novel therapies

The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population

Fibroblast growth factor 23 is independently associated with renal magnesium handling in patients with chronic kidney disease.

BACKGROUND: Disturbances in magnesium homeostasis are common in patients with chronic kidney disease (CKD) and are associated with increased mortality. The kidney is a key organ in maintaining normal serum magnesium concentrations. To this end, fractional excretion of magnesium (FEMg) increases as renal function declines. Despite recent progress, the hormonal regulation of renal magnesium handling is incompletely understood. Fibroblast Growth Factor 23 (FGF23) is a phosphaturic hormone that has been linked to renal magnesium handling. However, it has not yet been reported whether FGF23 is associated with renal magnesium handling in CKD patients. METHODS: The associations between plasma FGF23 levels, plasma and urine magnesium concentrations and FEMg was investigated in a cross-sectional cohort of 198 non-dialysis CKD patients undergoing renal biopsy. RESULTS: FGF23 was significantly correlated with FEMg (Pearson's correlation coefficient = 0.37, p<0.001) and urinary magnesium (-0.14, p=0.04), but not with plasma magnesium. The association between FGF23 and FEMg remained significant after adjusting for potential confounders, including estimated glomerular filtration rate (eGFR), parathyroid hormone and 25-hydroxyvitamin D. CONCLUSIONS: We report that plasma FGF23 is independently associated with measures of renal magnesium handling in a cohort of non-dialysis CKD patients. A potential causal relationship should be investigated in future studies

Is fetuin-A a mortality risk factor in dialysis patients or a mere risk marker? A Mendelian randomization approach

Background. Low levels of circulating fetuin-A are associated with increased mortality in dialysis patients. This study aimed to examine a potential causative role for fetuin-A on mortality by investigating whether a functional polymorphism in the alpha2-Heremans-Schmid glycoprotein (AHSG) gene associates with mortality, and by estimating the causative effect of fetuin-A levels on mortality using a Mendelian randomization design. Methods. One thousand and forty-three incident dialysis patients were genotyped for the Thr256Ser polymorphism (rs4918) and followed up for 5 years; in 549 patients, serum fetuin-A levels were measured. Results. Carriers of a serine allele displayed lower fetuin-A levels (-0.07 g/L per allele, P < 0.001). A small increased mortality risk was observed for the Thr/Ser and Ser/Ser genotype compared with the Thr/Thr genotype (HR 1.03, 95% CI 0.83-1.28 and HR 1.10, 95% CI 0.78-1.55, respectively). Using the AHSG genotype as an instrumental variable, the causative HR of fetuin-A levels on mortality was estimated as 1.01 per 0.1-g/L increase. Inflammation and diabetes partially modified the association of fetuin-A levels with outcome. Conclusions. The Thr256Ser polymorphism was weakly associated with mortality, and no causative effect of fetuin-A levels on this outcome was observed. Other risk factors, including inflammation and diabetes, might lead to lower fetuin-A levels, and/or modify the effect of low fetuin-A on mortality in end-stage renal disease patients.Clinical epidemiolog