The recently updated 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias set new, ambitious goals for lipid lowering based on recently ...generated evidence from large outcome trials. Noninvasive imaging as well as measurement of lipoprotein(a) as a non-traditional risk factor is advocated for the refinement of risk stratification. A highly potent statin - defined as a drug that lowers LDL-cholesterol by 50 % from baseline - is recommended as the standard choice of treatment, whenever medical lipid lowering is indicated. Combining different therapeutic strategies such as a statin with ezetimibe and/or a Proproteinkonvertase Subtilisin Kexin Type 9 inhibitor allows to achieve the new treatment targets. If needed, lipid apheresis can complement the medical armamentarium. Moreover, lipid apheresis remains the only approved treatment modality for lowering lipoprotein(a), however medical treatments are under current investigation.
Immunosuppression and monocyte subsets Rogacev, Kyrill S; Zawada, Adam M; Hundsdorfer, Johanna ...
Nephrology, dialysis, transplantation
30, Številka:
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Journal Article
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Monocytes are critical in innate immunity and transplantation. Three monocyte subsets exist, CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+)CD16(++) monocytes; cell counts of CD14(++)CD16(+) and ...CD14(+)CD16(++) monocytes are increased in pre-transplant chronic kidney disease. Interestingly, the effect of immunosuppressants on monocyte heterogeneity has not been well studied.
The impact of immunosuppressants on monocyte subsets was studied: (i) in 152 kidney transplant (KTx) recipients to characterize subset distribution in the steady state, (ii) in patients after autologous (n = 10) versus allogenic (n = 9) haematopoietic stem cell transplantation (HSCT) to analyse monocyte subset development and (iii) in an in vitro model to compare the effect of immunosuppressants on monocyte subset biology.
In KTx, steroid intake was associated with higher total, CD14(++)CD16(-) and CD14(++)CD16(+) monocyte counts, but fewer CD14(+)CD16(++) monocytes, whereas intake of mycophenolate, calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORI) did not affect monocyte (subset) counts. In linear regression analysis, only steroid intake was a significant determinant of monocyte (subset) counts: total monocytes (β = 0.331; P < 0.001), CD14(++)CD16(-) monocytes (β = 0.374; P < 0.001), CD14(++)CD16(+) monocytes (β = 0.221; P = 0.010) and CD14(+)CD16(++) monocytes (β = -0.169; P = 0.049). After HSCT, CD14(++)CD16(-) monocytes were the first to arise, followed by CD14(++)CD16(+) and later by CD14(+)CD16(++) monocytes. Monocyte subset distribution did not differ significantly in patients after allogenic compared with autologous transplantation. CNI, mycophenolate and methotrexate did not influence monocyte subset development, but modified surface receptor expression (CCR2, HLA-DR, ENG, TEK and TLR4) in allogenic HSCT.
Chronic low-dose steroids are associated with monocytosis and higher counts of CD14(++)CD16(-) and of proinflammatory CD14(++)CD16(+) monocytes.
Abstract Atherosclerosis has been characterized as an inflammatory process, in which monocytes and monocyte-derived macrophages are of paramount importance. Contrasting with their established role in ...atherosclerosis, monocytes have not unanimously been found to predict cardiovascular events in large epidemiological studies. However, in these studies human monocyte heterogeneity has been largely overlooked so far. Three human monocyte subsets can be distinguished: classical CD14++ CD16− , intermediate CD14++ CD16+ and nonclassical CD14+ CD16++ monocytes. Of note, correct enumeration of subset counts requires appropriate staining and gating strategies that encompass a pan-monocytic marker ( e.g. HLA-DR or CD86). In experimental studies on murine atherogenesis a monocyte subset-specific contribution to atherosclerosis has been established. However, major interspecies differences in atherogenesis itself, as well as in the immune system (including monocyte subset phenotype and distribution) preclude a direct extrapolation to human pathology. Experimental and pilot clinical studies point to a prominent involvement of intermediate CD14++ CD16+ monocytes in human atherosclerosis. Future clinical studies should analyze monocyte heterogeneity in cardiovascular disease. If a specific contribution of intermediate monocytes should be confirmed, immunomodulation of this monocyte subset could represent a future therapeutic target in atherosclerosis.
Aims Monocytes and monocyte-derived macrophages have been recognised as the cellular hallmark of atherosclerosis decades ago. Recently, they have also been shown to play a pivotal role in obesity. ...Monocytes display immunophenotypic heterogeneity with functionally distinct subpopulations. We initiated the I LIKE HOMe study to examine monocyte heterogeneity in obesity and subclinical atherosclerosis. Methods and results We assessed carotid intima media thickness (IMT), body mass index (BMI), and other cardiovascular risk factors in 622 healthy volunteers. Using flow-cytometry, we differentiated monocytes into CD14++CD16− and CD16+ cells, which we further subdivided into CD14++CD16+ and CD14(+)CD16+ cells. Body mass index was significantly correlated with carotid IMT. High CD16+ monocyte counts were significantly associated with both higher BMI and increased carotid IMT. Adjustment for CD16+ monocyte counts weakened the correlation between BMI and carotid IMT, suggesting that the increase in CD16+ monocyte numbers in obesity may partly explain the association between obesity and IMT. Conclusion Our results reveal a significant univariate association between CD16+ monocytes and both obesity and subclinical atherosclerosis in low-risk individuals. They are in line with recent observations that CD16+ monocytes show high endothelial affinity and a potent capacity to invade vascular lesions and to transform into pro-inflammatory cytokine producing macrophages.
Natriuretic peptides and echocardiographic parameters both predict cardiovascular events in patients with CKD. However, it is unknown whether simultaneous assessment of amino-terminal probrain ...natriuretic peptide (NT-proBNP) and echocardiographic parameters provides complementary or redundant predictive information; in the latter case, one of these two might be dispensable. We aimed to analyze the implications of using NT-proBNP alone, echocardiographic parameters alone, or a combination of both for prediction of adverse cardiovascular outcome.
Within the longitudinal Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation Study, we prospectively studied 496 patients with CKD stages G2-G4, in whom we measured NT-proBNP. Left ventricular mass index, left atrial volume index, diastolic left ventricular function, and systolic left ventricular function were assessed echocardiographically. During 4.5±2.0 years of follow-up, the occurrence of (1) decompensated heart failure or all-cause mortality and (2) atherosclerotic events or all-cause mortality was recorded. We assessed the association of NT-proBNP and echocardiographic parameters with outcome (using Cox models) and evaluated the increased discriminative value associated with the addition of echocardiographic parameters and NT-proBNP (using integrated discrimination improvement and net reclassification improvement).
During follow-up, 104 patients suffered decompensated heart failure or all-cause mortality, and 127 patents had atherosclerotic events or all-cause mortality. In univariable analyses, NT-proBNP and echocardiographic parameters predicted cardiovascular events. NT-proBNP remained an independent predictor for both end points in multivariate analysis, whereas left ventricular mass index, left atrial volume index, and diastolic left ventricular function did not. The addition of NT-proBNP on top of clinical and various echocardiographic variables was associated with improvements in reclassification for decompensated heart failure or all-cause mortality (integrated discrimination improvement =6.5%-8.3%; net reclassification improvement =23.1%-27.0%; all P≤0.03). Adding echocardiographic variables on top of clinical variables and NT-proBNP was not associated with significant net reclassification improvement (all P>0.05).
Our data confirm NT-proBNP is an independent predictor of adverse outcomes in patients with CKD. The additional use of echocardiography for improvement of risk stratification is not supported by our results.
Iron deficiency contributes to anaemia in patients with chronic kidney disease. I.v. iron is therefore widely used for anaemia treatment, although it may induce oxidative stress and activate ...monocytes. Different i.v. iron preparations are available, but interestingly their substance-specific immunologic effects are poorly studied.
We analysed the effect of iron sucrose, ferric carboxymaltose, iron isomaltoside 1000, low-molecular-weight iron dextran and ferumoxytol on classical, intermediate and nonclassical monocyte biology. We therefore stimulated in vitro mature monocytes and haematopoietic CD34(+) stem cells during their differentiation into monocytes with different concentrations (0.133, 0.266, 0.533 mg/mL) of i.v. iron preparations. Alterations of monocyte subset distribution, expression of surface markers (CD86, CCR5, CX3CR1), as well as production of pro-inflammatory cytokines (TNF-α, IL-1β) and reactive oxygen species were measured using flow cytometry. Additionally, we analysed phagocytosis and antigen presentation capacity.
We found specific immunologic effects after stimulation with iron sucrose which were not induced by the other iron preparations. Iron sucrose activated monocyte subsets leading to significantly increased CD86 expression. Simultaneously CD16 and CX3CR1 expression and monocytic phagocytosis capacity were decreased. Additionally, differentiation of monocytes from haematopoietic CD34(+) stem cells was almost completely abolished after stimulation with iron sucrose.
Our findings demonstrate that specific immunologic effects of distinct i.v. iron preparations exist. The clinical relevance of these findings requires further investigation.
Recent clinical trials on cholesterol-lowering in patients with CKD yielded conflicting results, which might have resulted from different treatment strategies. Serum cholesterol levels are determined ...by endogenous synthesis and intestinal absorption, which are differentially influenced by various classes of cholesterol-lowering agents. Assessing markers of cholesterol metabolism has thus been proposed for guidance of lipid-lowering therapy. This study analyzed surrogate markers of cholesterol absorption and synthesis in hemodialysis (HD) patients.
In 113 HD patients, lathosterol was measured as a marker of cholesterol synthesis and cholestanol was measured as a marker of cholesterol absorption via gas chromatography. Controls were 229 healthy persons. Overall survival in HD patients was recorded over 3.4-year follow-up.
Compared with controls, HD patients had lower lathosterol and higher cholestanol levels (P<0.001 for both). During follow-up, 58 patients died; higher cholestanol (indicating higher cholesterol absorption) predicted poor outcome among HD patients in multivariate Cox regression analysis after adjustment for potential confounders (hazard ratio for cholestanol above median, 2.24 95% confidence interval (CI), 1.29-3.89; P=0.004), whereas lower lathosterol (indicating lower cholesterol synthesis) did not (hazard ratio for lathosterol below median, 1.43 95% CI, 0.81-2.50; P=0.22).
This analysis of markers of cholesterol metabolism characterizes HD patients as cholesterol absorbers. In longitudinal analysis, higher levels of cholestanol were associated with all-cause mortality.
Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of ...atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL‐cholesterol, nor the key parameter of HDL‐cholesterol function—that is, cholesterol efflux capacity—predicts future cardiovascular events. Therefore, HDL‐cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL‐cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL‐cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL‐cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients.
The relationship of cholesterol homeostasis and carotid intima-media thickness (cIMT) is unknown. To address this, we assessed markers of cholesterol homeostasis (serum plant sterols and cholesterol ...precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) and cIMT in a middle-aged, statin-naive population.
In this prospective study of primary prevention cIMT was measured by ultrasound in 583 hospital employees aged 25-60 years without prevalent cardiovascular disease or lipid-modifying medication. The serum concentrations of plant sterols (as markers of cholesterol absorption) were measured by gas-liquid chromatography. Lathosterol serum concentrations were quantitated to assess hepatic cholesterol synthesis.
cIMT correlated positively with serum cholesterol (r = 0.22, P<0.0005) and lathosterol-to-cholesterol (r = 0.18, P<0.001). In contrast, plant sterols, as markers of cholesterol absorption, showed a weak negative correlation to cIMT measurements (r = -0.18; P<0.001 for campesterol-to-cholesterol). Stratifying subjects by serum sterol levels, we found that cIMT increased continuously over quintiles of serum cholesterol (P<0.0005) and was positively associated to serum lathosterol-to-cholesterol levels (P = 0.007), on the other hand, plant sterol levels showed a weak negative association to cIMT (P<0.001 for campesterol-to-cholesterol).
In this population without prevalent cardiovascular diseases or lipid-modifying medication, markers of increased endogenous cholesterol synthesis correlated positively with cIMT, while markers of cholesterol absorption showed a weakly negative correlation. These data suggest that not only total serum cholesterol levels but also differences in cholesterol homeostasis are associated with cIMT.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human monocytes are a heterogeneous cell population consisting of 3 subsets: classical CD14++CD16-, intermediate CD14++CD16+ and nonclassical CD14+CD16++ monocytes. Via poorly characterized ...mechanisms, intermediate monocyte counts rise in chronic inflammatory diseases, among which chronic kidney disease is of particular epidemiologic importance. DNA methylation is a central epigenetic feature that controls hematopoiesis. By applying next-generation Methyl-Sequencing we now tested how far the 3 monocyte subsets differ in their DNA methylome and whether uremia induces DNA methylation changes in differentiating monocytes. We found that each monocyte subset displays a unique phenotype with regards to DNA methylation. Genes with differentially methylated promoter regions in intermediate monocytes were linked to distinct immunological processes, which is in line with results from recent gene expression analyses. In vitro, uremia induced dysregulation of DNA methylation in differentiating monocytes, which affected several transcription regulators important for monocyte differentiation (e.g., FLT3, HDAC1, MNT) and led to enhanced generation of intermediate monocytes. As potential mediator, the uremic toxin and methylation inhibitor S-adenosylhomocysteine induced shifts in monocyte subsets in vitro, and associated with monocyte subset counts in vivo. Our data support the concept of monocyte trichotomy and the distinct role of intermediate monocytes in human immunity. The shift in monocyte subsets that occurs in chronic kidney disease, a proinflammatory condition of substantial epidemiological impact, may be induced by accumulation of uremic toxins that mediate epigenetic dysregulation.
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