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The monocyte continuum and cardiovascular disease: Evaluation of the prognostic cardiovascular meaning of monocyte displacement along their continuum
Full text linkIntroduction. Monocytes are cells of the innate immunity system with high heterogeneity and plasticity and are involved in acute and chronic inflammatory states. Monocytes are traditionally distinguished in three subsets, based on CD14 (LPS co-receptor) and CD16 (FcγIII receptor with low IgG affinity) expression: classical, intermediate and non-classical. Monocyte subsets have a developmental relationship and differ in phenotypic and functional characteristics. Distribution of monocyte subsets has been shown to predict cardiovascular outcomes. Nevertheless, monocytes have now been redefined as a continuum of subsets with dynamic changes of their characteristics and classification into different subtypes may be an oversimplification. Monocytes have been studied in cardiovascular diseases because they are involved in inflammatory processes linked with these pathological states: they have a central role in the development of atherosclerotic plaques, that represent the major cause of cardiovascular events. Changes within different monocyte subsets are reported in several studies in relation with cardiovascular risk factors and cardiovascular diseases.
Aim of the study. The aim of this study is to establish whether distribution of monocytes based on CD14 and CD16 fluorescence intensity provides incremental and complementary information in relation to cardiovascular risk factors, prevalent cardiovascular diseases and cardiovascular outcomes beyond enumeration of traditional subsets.
Materials and methods. A cohort of 227 patients with high cardiovascular risk (patients with at least two classical cardiovascular risk factors or with establish cardiovascular disease) were recruited for this study and followed up for a median of 4 years. Monocyte subsets were quantified and characterized at baseline using polychromatic flow cytometry, based on the CD14 e CD16 expression; for each monocyte subset frequency and mean fluorescence intensity (MFI) of CD14 and CD16 were determined, evaluating the continuous distribution. These monocyte characteristics were studied in patients in relation to cardiovascular risk factors, prevalence of coronary artery disease (CAD) and occurrence of major adverse cardiovascular events (MACE) during follow-up.
Results. In relation to cardiovascular risk factors, every monocyte subset of patients with type 2 diabetes showed a consistent shift toward higher CD16 fluorescence intensity, despite no changes in their frequencies. Patients with coronary artery disease (CAD) at baseline displayed a doubled amount of CD14++ CD16+, intermediate monocytes, and a shift of non-classical and classical monocytes towards intermediates ones. During follow-up, cardiovascular death or cardiovascular events occurred in 26 patients, who showed monocyte displacement similar to those of patients with CAD at baseline. Using a Cox proportional hazard regression models, among monocytes parameters, only the higher CD16 expression on classical monocytes, independently predicted adverse cardiovascular outcomes, but not the level of intermediate monocytes or other subsets.
Discussion and conclusion. Changes within monocyte subsets in patients with CAD and in patients with incident MACE during follow-up suggested a shift of classical and non-classical monocytes towards intermediate monocytes, showing phenotypic changes within the monocyte continuum. The predictive role of CD16 MFI on classical monocytes highlights how the concept of monocyte continuum can be used to shape the cardiovascular risk more than frequencies of monocyte subsets can do.Introduzione. I monociti sono cellule del sistema dell’immunità innata con elevata eterogeneità e plasticità e sono coinvolti in stati infiammatori acuti e cronici. I monociti sono tradizionalmente distinti in tre sottopopolazioni, in base all'espressione del CD14 (co-recettore dell’LPS) e CD16 (recettore FcγIII con bassa affinità per IgG): classici, intermedi e non classici. Questi sottogruppi monocitari hanno una relazione evolutiva e differiscono per caratteristiche fenotipiche e funzionali. La distribuzione dei sottoinsiemi monocitari ha dimostrato di prevedere gli esiti cardiovascolari. Tuttavia, i monociti sono recentemente stati ridefiniti come un continuum di sottoinsiemi con cambiamenti dinamici delle loro caratteristiche e la categorizzazione in sottoinsiemi discreti può essere considerata come un’eccessiva semplificazione. Nelle malattie cardiovascolari i monociti sono stati studiati in quanto coinvolti in processi infiammatori legati a questi stati patologici: hanno un ruolo centrale nello sviluppo delle placche aterosclerotiche, che rappresentano la principale causa per gli eventi cardiovascolari. Diversi studi hanno dimostrato cambiamenti all'interno dei sottoinsiemi monocitari in relazione ai tradizionali fattori di rischio cardiovascolare e alle patologie cardiovascolari.
Scopo dello studio. Lo scopo di questo studio è stabilire se la distribuzione dei monociti basata sull'intensità di fluorescenza del CD14 e del CD16 fornisce informazioni incrementali e complementari in relazione ai fattori di rischio cardiovascolare, alle patologie cardiovascolari prevalenti e agli esiti cardiovascolari rispetto alla quantificazione della frequenza dei sottogruppi tradizionali. L'obiettivo dello studio è anche quello di verificare se questi cambiamenti predicono esiti cardiovascolari.
Materiali e metodi. 227 pazienti ad alto rischio cardiovascolare (pazienti con almeno due classici fattori di rischio cardiovascolare o con malattia cardiovascolare stabilita) sono stati reclutati per questo studio e seguiti per una mediana di 4 anni. Le sottopopolazioni monocitarie sono state quantificate e caratterizzate al basale utilizzando la citometria a flusso policromatica, in base all'espressione di CD14 e CD16; per ciascun sottogruppo sono stati determinati la frequenza e l’ intensità media di fluorescenza (MFI) di CD14 e CD16, valutando la loro distribuzione lungo il continuum monocitario. Queste caratteristiche dei monociti sono state studiate nei pazienti correlandole ai fattori di rischio cardiovascolare, alla prevalenza di malattia coronarica (CAD) e alla comparsa di eventi avversi cardiovascolari maggiori (MACE) durante il follow-up.
Risultati. In relazione ai fattori di rischio cardiovascolare, nei pazienti con diabete di tipo 2 è stato osservato un aumento consistente dell’ intensità di fluorescenza del CD16 all'interno di ciascun gruppo di monociti, nonostante non si sia rilevato nessun cambiamento nelle loro frequenze. I pazienti con malattia coronarica (CAD) al basale hanno mostrato un raddoppio nella frequenza dei monociti intermedi CD14++ CD16+ e uno spostamento di monociti classici e non classici verso quelli intermedi. Durante il follow-up, la morte cardiovascolare o eventi cardiovascolari si sono verificati in 26 pazienti, che hanno mostrato uno spostamento dei monociti simile a quelli dei pazienti con CAD al basale. Utilizzando il modello di Cox di regressione di rischio proporzionale, tra i parametri dei monociti, solo l'espressione del CD16, più elevata sui monociti classici, ma non il livello di monociti intermedi o di altri sottogruppi, predice indipendentemente gli eventi cardiovascolari avversi.
Discussione e conclusione. I cambiamenti nei sottogruppi monocitari in pazienti con CAD e in pazienti evoluti in MACE durante il follow-up hanno suggerito uno “shift” dei monociti classici e non classici verso gli intermedi, mostrando cambiamenti fenotipici all'interno del continuum monocitario. Il ruolo predittivo dell’MFI del CD16 sui monociti classici evidenzia come il concetto di continuum monocitario possa essere utilizzato per modellare il rischio cardiovascolare più della frequenza delle diverse sottopopolazioni monocitarie
Plerixafor improves the endothelial health balance. The effect of diabetes analysed by polychromatic flow cytometry
No full textBACKGROUND AND AIMS:
Diabetes damages the endothelium and reduces the availability of bone marrow (BM)-derived endothelial progenitor cells (EPCs). The mobilization of hematopoietic stem cells (HSCs) and EPCs in response to G-CSF is impaired by diabetes, owing to CXCL12 dysregulation. We have previously shown that the CXCR4/CXCL12 disruptor plerixafor rescues HSC and EPC mobilization in diabetes. We herein explored the effects of plerixafor on HSCs, EPCs, and circulating endothelial cells (CECs) in patients with and without diabetes.
METHODS:
We re-analysed data gathered in the NCT02056210 trial, wherein patients with (n = 10) and without diabetes (n = 10) received plerixafor to test stem/progenitor cell mobilization. We applied a novel and very specific polychromatic flow cytometry (PFC) approach to identify and quantify HSCs, EPCs, and CECs.
RESULTS:
We found that 7-AAD(-)Syto16(+)CD34(+)CD45(dim) HSC levels determined by PFC strongly correlated to the traditional enumeration of CD34(+) cells, whereas 7-AAD(-)Syto16(+)CD34(+)CD45(neg)KDR(+) EPCs were unrelated to the traditional enumeration of CD34(+)KDR(+) cells. Using PFC, we confirmed that plerixafor induces rapid mobilization of HSCs and EPCs in both groups, with a marginally significant defect in patients with diabetes. Plerixafor reduced live (7-AAD(-)) and dead (7-AAD(+)) Syto16(+)CD34(bright)CD45(neg)CD146(+) CECs more in patients without than in those with diabetes. The EPC/CEC ratio, a measure of the vascular health balance, was increased by plerixafor, but less prominently in patients with that in those without diabetes.
CONCLUSIONS:
In addition to rescuing defective mobilization associated with diabetes, plerixafor improves the balance between EPCs and CECs, but the latter effect is blunted in patients with diabetes
The continuum of monocyte phenotypes: Experimental evidence and prognostic utility in assessing cardiovascular risk
No full textThe monocyte-macrophage cell lineage represents a major player in innate immunity, and is involved in many physiologic and pathologic conditions. Particularly, monocyte-macrophages play a very important role in atherosclerosis and cardiovascular disease. Monocyte heterogeneity is well recognized but the biologic and clinical meaning of the various monocyte subtypes is not entirely understood. Traditionally, monocytes can be divided in classical, intermediate, and nonclassical based on expression of the surface antigens CD14 and CD16. While macrophage diversity is now well recognized to organize as a continuum, monocyte subsets have long been considered as separated entities. However, mounting evidence obtained by tracking the ontology of human monocytes help clarifying that monocytes mature from classical to nonclassical ones, through an intermediate phenotype. This concept is therefore best depicted as a continuum, whereas the subdivision into discrete CD14/CD16 subsets appears an oversimplification. In this review, we discuss the evidence supporting the existence of a monocyte continuum along with the technical challenges of monocyte characterization. In particular, we describe the advantage of considering monocytes along a continuous distribution for the evaluation of cardiovascular risk. We make the point that small transition along the monocyte continuum better reflects cardiovascular risk than a simplified analysis of discrete monocyte subsets. Recognizing the monocyte continuum can be helpful to model other pathophysiologic conditions where these cells are involved
Long-term Prediction of Cardiovascular Outcomes by Circulating CD34+ and CD34+CD133+ Stem Cells in Patients With Type 2 Diabetes
No full textOBJECTIVE:
Cardiovascular risk varies substantially in the population with diabetes, and biomarkers can improve risk stratification. Circulating stem cells predict future cardiovascular events and death, but data for the population with diabetes are scant. In this study we evaluated the ability of circulating stem cell levels to predict future cardiovascular outcomes and improve risk discrimination in patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS:
A cohort of 187 patients with type 2 diabetes was monitored for a median of 6.1 years. The primary outcome was time to a first cardiovascular event, defined as 3-point major adverse cardiovascular event (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) plus hospitalization for cardiovascular causes. At baseline, we measured six stem/progenitor cell phenotypes in peripheral blood based on expression of CD34, CD133, and KDR.
RESULTS:
The primary outcome occurred in 48 patients (4.5/100 patient-years). Patients with incident cardiovascular events had significantly lower CD34+ and CD34+CD133+ cells than those without. Higher rates of cardiovascular events occurred in patients with below median levels of CD34+ and CD34+CD133+. In Cox proportional hazard regression analyses, a reduced CD34+ (hazard ratio 2.21 [95% CI 1.14-4.29]) and CD34+CD133+ (2.98 [1.46-6.08]) cell count independently predicted future events. Addition of the CD34+ cell count to the reference model or the UK Prospective Diabetes Study risk engine improved C statistics, continuous net reclassification improvement, and/or integrated discrimination index.
CONCLUSIONS:
In patients with type 2 diabetes, a reduced baseline level of circulating CD34+ stem cells predicts adverse cardiovascular outcomes up to 6 years later and improves risk stratificatio
Effects of SGLT2 inhibitors on circulating stem and progenitor cells in patients with type 2 diabetes
No full text
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Glycaemic Control Achieves Sustained Increases of Circulating Endothelial Progenitor Cells in Patients Hospitalized for Decompensated Diabetes: An Observational Study
Full text linkDiabetes reduces the levels of circulating endothelial progenitor cells (EPCs), which contribute to vascular homeostasis. In turn, low EPCs levels predict progression of chronic complications. Several studies have shown that hyperglycaemia exerts detrimental effects on EPCs. Improvement in glucose control with glucose-lowering medications is associated with an increase of EPCs, but only after a long time of good glycaemic control. In the present study, we examined the effect of a rapid glycaemic amelioration on EPC levels in subjects hospitalized for decompensated diabetes
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