Monocytes are a heterogeneous cell population with subset-specific functions and phenotypes. The differential expression of CD14 and CD16 distinguishes classical CD14++CD16−, intermediate ...CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Current knowledge on human monocyte heterogeneity is still incomplete: while it is increasingly acknowledged that CD14++CD16+ monocytes are of outstanding significance in 2 global health issues, namely HIV-1 infection and atherosclerosis, CD14++CD16+ monocytes remain the most poorly characterized subset so far. We therefore developed a method to purify the 3 monocyte subsets from human blood and analyzed their transcriptomes using SuperSAGE in combination with high-throughput sequencing. Analysis of 5 487 603 tags revealed unique identifiers of CD14++CD16+ monocytes, delineating these cells from the 2 other monocyte subsets. Gene Ontology (GO) enrichment analysis suggests diverse immunologic functions, linking CD14++CD16+ monocytes to Ag processing and presentation (eg, CD74, HLA-DR, IFI30, CTSB), to inflammation and monocyte activation (eg, TGFB1, AIF1, PTPN6), and to angiogenesis (eg, TIE2, CD105). In conclusion, we provide genetic evidence for a distinct role of CD14++CD16+ monocytes in human immunity. After CD14++CD16+ monocytes have earlier been discussed as a potential therapeutic target in inflammatory diseases, we are hopeful that our data will spur further research in the field of monocyte heterogeneity.
Objectives The aim of this study was to analyze the yet ill-defined relationship of distinct human monocyte subsets with cardiovascular outcomes in a broad patient population at cardiovascular risk. ...Background Monocytes, the most abundant immune cell type found in atherosclerotic plaques, are crucial promoters of atherogenesis. Three distinct human monocyte subsets exist: classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Immunomodulation of distinct monocyte subsets has recently been discussed as a new therapeutic avenue in atherosclerosis. Methods Cardiovascular events in 951 subjects referred for elective coronary angiography were prospectively analyzed. Monocyte subset analysis was performed using flow cytometry, blinded to patients' clinical characteristics, and patients were categorized according to quartiles of total monocyte and monocyte subset counts. The primary endpoint was defined a priori as the first occurrence of cardiovascular death, acute myocardial infarction, or nonhemorrhagic stroke. Endpoint adjudication was done blinded to monocyte subset distribution. Results During a mean follow-up period of 2.6 ± 1.0 years, 93 patients experienced the primary endpoint. In univariate Kaplan-Meier analysis, counts of total (p = 0.010), classical CD14++CD16− (p = 0.024), and intermediate CD14++CD16+ (p < 0.001) monocytes predicted the primary endpoint, whereas nonclassical monocytes did not (p = 0.158). After full adjustment for confounders, CD14++CD16+ monocytes remained the only monocyte subset independently related to cardiovascular events (fourth vs. first quartile: hazard ratio: 3.019; 95% confidence interval: 1.315 to 6.928; p = 0.009). Conclusions CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography. Future studies will be needed to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies in atherosclerosis.
The aim of this study was to analyze the yet ill-defined relationship of distinct human monocyte subsets with cardiovascular outcomes in a broad patient population at cardiovascular risk.
Monocytes, ...the most abundant immune cell type found in atherosclerotic plaques, are crucial promoters of atherogenesis. Three distinct human monocyte subsets exist: classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Immunomodulation of distinct monocyte subsets has recently been discussed as a new therapeutic avenue in atherosclerosis.
Cardiovascular events in 951 subjects referred for elective coronary angiography were prospectively analyzed. Monocyte subset analysis was performed using flow cytometry, blinded to patients' clinical characteristics, and patients were categorized according to quartiles of total monocyte and monocyte subset counts. The primary endpoint was defined a priori as the first occurrence of cardiovascular death, acute myocardial infarction, or nonhemorrhagic stroke. Endpoint adjudication was done blinded to monocyte subset distribution.
During a mean follow-up period of 2.6 ± 1.0 years, 93 patients experienced the primary endpoint. In univariate Kaplan-Meier analysis, counts of total (p = 0.010), classical CD14++CD16- (p = 0.024), and intermediate CD14++CD16+ (p < 0.001) monocytes predicted the primary endpoint, whereas nonclassical monocytes did not (p = 0.158). After full adjustment for confounders, CD14++CD16+ monocytes remained the only monocyte subset independently related to cardiovascular events (fourth vs. first quartile: hazard ratio: 3.019; 95% confidence interval: 1.315 to 6.928; p = 0.009).
CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography. Future studies will be needed to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies in atherosclerosis.
Patients with chronic kidney disease (CKD) pose a worldwide growing burden to health care systems due to accelerated atherosclerosis and subsequent high cardiovascular (CV) morbidity. Atherogenesis ...is prominently driven by monocytes and monocyte-derived macrophages. The expression of CD14 and CD16 characterizes three monocyte subsets: CD14(++)CD16(-), CD14(++)CD16(+), and CD14((+))CD16(+) cells; the latter two are often denoted as 'proinflammatory' CD16(+) monocytes. Despite an association between CD16(+) monocyte counts and higher CV risk in cross-sectional cohorts, the prognostic impact of elevated CD16(+) monocyte counts is poorly understood.
We assessed monocyte heterogeneity using flow cytometry in 119 patients with non-dialysis CKD, who were prospectively followed for a median of 4.9 (inter-quartile range 4.8-5.0) years for the occurrence of CV events. In addition, we assessed expression of chemokine receptors on monocyte subsets. CD14(++)CD16(+) monocyte were independently associated with CV events hazard ratio (for an increase of 10 cells/μL) 1.26 (confidence interval: 1.04-1.52; P = 0.018) after adjustment for variables that significantly affected CD14(++)CD16(+) cell counts at baseline. Across the spectrum of CKD, CD14(++)CD16(+) monocytes selectively expressed CCR5.
We found that CD14(++)CD16(+) monocytes were independently associated with CV events in non-dialysis CKD patients. Our results support the notion that CD16(+) monocytes rather than CD16(-) monocytes are involved in human atherosclerosis.
Recent clinical studies have shown a strong correlation between in vitro cholesterol efflux capacity (CEC) and cardiovascular disease prevalence (1) and incidence (2,3) that seems to be independent ...of high-density lipoprotein cholesterol (HDL-C) levels. ...our results suggest that CEC is not a prognostic cardiovascular risk marker in patients with CKD.
Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) ...is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored.
Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths.
PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 1.8-4.1 years and 10.0 7.3-10.6 years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort CARE FOR HOMe (p = 0.622); LURIC (p = 0.729). Sensitivity analyses according to statin intake yielded similar results.
In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert ...direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.
Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.
Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio HR for third versus first sKlotho tertile, 0.75 95% confidence interval (95% CI), 0.43-1.30; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 95% CI, 0.39-1.66; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 95% CI, 0.58-2.61; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 95% CI, 1.33-15.21; P=0.02).
In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which ...substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
OBJECTIVE—Patients with chronic kidney disease (CKD) display impaired cholesterol efflux capacity and elevated CD14CD16 monocyte counts. In mice, dysfunctional cholesterol efflux causes monocytosis. ...It is unknown whether cholesterol efflux capacity and monocyte subsets are associated in CKD.
APPROACH AND RESULTS—In 438 patients with CKD, mediators of cholesterol efflux capacity (high-density lipoprotein cholesterol/apolipoprotein A-I) and monocyte subsets were analyzed as predictors of cardiovascular events. Monocyte subset-specific intracellular lipid content, CD36, CD68, and ABCA1 were measured in a subgroup. Experimentally, we analyzed subset-specific cholesterol efflux capacity and response to oxidized low-density lipoprotein cholesterol stimulation in CKD. Epidemiologically, both low Apo-I and low high-density lipoprotein cholesterol were associated with high CD14CD16 monocyte counts in linear regression analyses (apolipoprotein A-Iβ=−0.171; P<0.001; high-density lipoprotein cholesterolβ=−0.138; P=0.005), but not with counts of other monocyte subsets. In contrast to apolipoprotein A-I or high-density lipoprotein cholesterol, higher CD14CD16 monocyte counts independently predicted cardiovascular events (hazard ratio per increase of 1 cell/μL1.011 1.003–1.020; P=0.007). Experimentally, CD14CD16 monocytes demonstrated preferential lipid accumulation, high CD36, CD68, and low ABCA1 expression and, consequently, displayed low cholesterol efflux capacity, avid oxidized low-density lipoprotein cholesterol uptake, and potent intracellular interleukin-6, interleukin-1β, and tumor necrosis factor-α production.
CONCLUSIONS—Taken together, mediators of cholesterol efflux are associated with CD14CD16 monocyte counts, which independently predict adverse outcome in CKD.
Chronic kidney disease (CKD), which affects >10% of the population worldwide, is associated with a dramatically increased rate of cardiovascular disease (CVD). More people with CKD will die from CVD ...than develop end-stage renal disease with dialysis-dependency. However, the contribution of classical atherosclerotic cardiovascular risk factors is less evident than in the general population. Particularly, the relationship between dyslipidemia and CVD morbidity and mortality in CKD patients is not as evident as in the general population. While LDL cholesterol-lowering drugs such as statins significantly reduce the rate of cardiovascular events in the general population, their role in patients with end-stage renal disease has been questioned. This could be caused by a shift from atherosclerotic to non-atherosclerotic CVD in patients with advanced CKD, which cannot be effectively prevented by lipid-lowering drugs. In addition, many lines of evidence suggest that impaired renal function directly affects the metabolism, composition and functionality of lipoproteins, which may affect their responsiveness to pharmacological interventions. In this review, we highlight the challenges for the therapeutic application of lipid-lowering treatment strategies in CKD and discuss why treatment strategies used in the general population cannot be applied uncritically to CKD patients.
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