Benjamin J. Wrigley

The role of monocytes and inflammation in the pathophysiology of heart failure.

There is growing evidence to support an important role of inflammation in the underlying pathophysiology of heart failure (HF). Indeed, inflammatory cytokine levels are well recognized to be increased in patients with left ventricular dysfunction and appear to have prognostic implications. Monocytes play a pivotal role in the inflammatory cascade and are a major source of both pro‐ and anti‐inflammatory cytokines. They are intimately involved in tissue damage and repair and an imbalance of these processes may have detrimental consequences for the failing myocardium. Importantly, monocytes comprise of distinct subsets with different cell surface markers and functional characteristics and this heterogeneity may be important in understanding their specific role in HF. In HF, monocyte activation involves interplay between pattern recognition molecules, endotoxins, cytokines, and acute phase proteins. Activated monocytes migrate to the myocardium in response to powerful chemokines, where they must then attach to the endothelial wall before infiltrating into the myocardium itself. This review article aims to discuss the role of monocytes and inflammation in HF, focusing on monocyte activation, mobilisation, recruitment and endothelial adherence, as well as the effects they may have on myocardial performance. The therapeutic modulation of inflammation and monocyte activation in HF treatment will also be reviewed.

Immunophenotypic characterization of human monocyte subsets: possible implications for cardiovascular disease pathophysiology

Summary.  Objectives: Monocytes include several subsets with different and sometimes divergent roles in immunity, atherogenesis and reparative processes. Objectives: We aimed to perform detailed immunophenotypic and functional characterization of human monocyte subsets. Patients/methods: Analysis of surface markers of blood and bone marrow monocyte subsets and functional characterization of blood monocyte subsets in healthy volunteers was performed using flow cytometry. Results: In the present study, we show the presence of three subsets which could be unequivocally distinguished by surface expression of CD14, CD16 and CCR2 as CD14+CD16−CCR2+(Mon1), CD14+CD16+CCR2+(Mon2) and CD14lowCD16+CCR2−(Mon3) subsets. In comparison with the classic Mon1, the Mon2 subset had the highest expression of Tie2, CXCR4, CD163, CD115, receptors to inter‐cellular adhesion molecule‐1 (ICAM‐1), vascular endothelial growth factor (VEGF), and the highest surface levels of apolipoprotein B and ferritin. In contrast, Mon3 had maximal expression of VCAM‐1 receptors and CD204. The Mon2 and Mon3 subsets had significantly lower activity of the NFκB pathway than Mon1. Mon1 and Mon2 had similar phagocytic activity, which was significantly higher compared with Mon3. All three subsets were present in bone marrow, although the relative proportion of Mon2 in bone marrow was about 2.5‐fold higher compared with that seen in blood. Significant differences in cytokine production in response to endotoxin stimulation were observed between the three monocyte subsets. Conclusion: Given their immunophenotypic similarity, the newly characterized Mon2 population may represent the previously reported pluripotent progenitor/pro‐angiogenic monocytes.

The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction.

Summary.  Aim:  Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST‐elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI.

CD14++CD16+ monocytes in patients with acute ischaemic heart failure

Monocytes play important roles in inflammation, angiogenesis and tissue repair and may contribute to the pathophysiology of heart failure (HF).

A contemporary view on endothelial function in heart failure.

The assessment of different aspects of endothelial dysfunction in cardiovascular medicine in general and in heart failure (HF) has been the focus of intense research, and includes vasomotor, haemostatic, antioxidant, and inflammatory activities. Differences also exist in the pattern of endothelial dysfunction depending on aetiology, severity, and stability of HF in individual patients. In the majority of patients with ischaemic aetiology of HF, endothelial dysfunction is systemic in its nature and involves both arteries and veins, conductance vessels and microvascular beds, coronary, pulmonary, and peripheral vessels. The pattern of endothelial dysfunction is more heterogeneous in non‐ischaemic HF, with fewer features of systemic abnormalities. Indeed, many subjects with non‐ischaemic HF have a functionally preserved endothelium in peripheral arteries, with endothelial dysfunction seen only in coronary vessels. Endothelial dysfunction has significant prognostic value in HF, but its clinical application is hampered by methodological limitations in its assessment. Various medications (including angiotensin‐converting enzyme inhibitors and statins) and regular physical activity have been shown to improve endothelial function in HF. However, there are still no pharmaceutical agents specifically targeting the vascular endothelium. Despite the large number of studies, the pathophysiological role of the vascular endothelium and its clinical potential as a therapeutic target has not yet been sufficiently developed and undoubtedly awaits further exploration.

Monocyte subsets in coronary artery disease and their associations with markers of inflammation and fibrinolysis

AIMS The multiple roles of monocytes in atherogenesis, including inflammation, angiogenesis and repair are attributed to the existence of different monocyte sub-populations. Scarce data are available on changes in phenotype and functional status of human monocyte subsets in patients with coronary artery disease (CAD), especially when monocytes are evaluated as three distinct subsets. METHODS AND RESULTS Surface expression of receptors implicated in inflammation, repair and activation status (intracellular IKKβ) of monocyte subsets was assessed by flow cytometry in 53 patients with CAD and compared to 50 age- and sex-matched healthy controls. Monocyte subsets were defined as CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2), and CD14+CD16++CCR2- (Mon3). Plasma levels of inflammatory cytokines (FACSArray) and fibrinolytic factors (ELISA) were measured in CAD. CAD was associated with reduced expression of CD14 on Mon1 (p = 0.02) and Mon3 (p = 0.036), higher expression of IL6 receptor on Mon1 (p = 0.025) and Mon2 (p = 0.015), CXCR4 on Mon1 (p = 0.035) and Mon3 (p = 0.003), and CD34 on all subsets (all p < 0.007). Monocyte CD163 expression correlated negatively with interleukin (IL)-6 levels (p < 0.01 for all subsets). Expression of vascular endothelial growth factor receptor-1 correlated positively with plasminogen activator inhibitor (PAI)-1 antigen levels (r = 0.47, p = 0.006). In vitro, monocyte subsets derived from CAD patients showed significantly altered responses to endotoxin stimulation compared to monocytes from healthy controls. CONCLUSIONS There is a complex interplay between phenotype and activity of monocytes and plasma cytokines and fibrinolytic factors. These findings support the presence of unique roles for the three human monocyte subsets in atherogenesis and CAD pathogenesis.

Increased Formation of Monocyte-Platelet Aggregates in Ischemic Heart Failure

Background— Cross-talk between monocytes and platelets is reflected by the formation of monocyte-platelet aggregates (MPAs). It is not known whether MPAs are affected in heart failure (HF), and we examined differences in patients with acute HF (AHF), stable HF (SHF), stable coronary artery disease (CAD) without HF, and healthy controls (HCs). Methods and Results— MPAs were analyzed by flow cytometry for the 3 monocyte subsets (CD14++CD16-CCR2+ [Mon1], CD14++CD16+CCR2+ [Mon2] and CD14+CD16++CCR2– [Mon3]) in patients with AHF (n=51), SHF (n=42), stable CAD (n=44), and HCs (n=40). Counts of total MPA and MPAs associated with Mon1 and Mon2 were significantly higher in AHF compared with SHF, CAD, and HCs (P<0.001 for all). The proportion of Mon1 aggregated with platelets was increased in AHF compared with SHF (P=0.033), CAD (P<0.001), and HCs (P<0.001). A higher percentage of Mon3 aggregated with platelets was also seen in AHF compared with SHF (P=0.012) and HCs (P<0.001) but not compared with CAD (P=0.647). MPAs associated with Mon2 were significantly lower in patients who experienced adverse clinical outcomes of death or rehospitalization compared with those who remained free of events (P=0.03). Mon2 count remained an independent negative predictor of combined death and rehospitalization after adjustment for age, left ventricular ejection fraction, creatinine, and brain natriuretic peptide (hazard ratio, 0.58 [95% CI, 0.34–0.98]; P=0.043). Conclusions— MPA formation in patients with both acute and stable HF is increased and seems to be confined to monocytes from Mon1 and Mon2 subsets. MPAs associated with Mon2 seem to be negatively predictive of a worse prognosis in AHF.

The effects of exercise and diurnal variation on monocyte subsets and monocyte‐platelet aggregates

Eur J Clin Invest 2012

TLR4 expression on monocyte subsets in myocardial infarction

Monocyte toll‐like receptor 4 (TLR4) has been implicated in the pathogenesis of atherosclerosis with increased levels in myocardial infarction. The aim of this study was to assess the numbers of TLR4+ monocytes in each monocyte subset in MI, the expression of TLR4 and association with markers of monocyte activation, inflammation, myocardial damage and postmyocardial infarction (MI) cardiac contractility.

Ethnic Differences in Macrovascular and Microvascular Function in Systolic Heart Failure

Background— Endothelial dysfunction is implicated in the pathophysiological features of heart failure (HF), and ethnic differences in the presentation of cardiovascular disease are evident, with an excess seen among South Asians (SAs). However, data on ethnic differences in endothelial function in HF are limited. Methods and Results— In a cross-sectional study, we recruited 128 subjects with systolic HF: 50 SAs, 50 whites, and 28 African Caribbeans (ACs). In addition, SAs with systolic HF were compared with 40 SAs with coronary artery disease without HF (“disease controls”) and 40 SA healthy controls. Macrovascular endothelial function was assessed by measurement of flow-mediated dilation (FMD) in response to hyperemia, arterial stiffness was assessed by the pulse-wave velocity, and microvascular endothelial function was assessed by forearm laser Doppler flowmetry. CD144-expressing endothelial microparticles were measured by flow cytometry. When compared with disease controls and healthy controls, SAs with HF had an impaired microvascular response to acetylcholine (P=0.001) and reduced FMD (P<0.001). In comparing ethnic groups, SAs with HF had an impaired response to acetylcholine (123±95.5%) compared with whites (258±156%) and ACs (286±173%, P<0.001 for both). Whites had a higher FMD (8.49±4.63%) than SAs (4.76±4.78%, P<0.001) and ACs (4.55±3.56%, P=0.01). No difference in endothelial-independent response was observed between study groups or in pulse-wave velocity. Ethnicity remained associated with microvascular endothelial function even after adjustment for age, presence of hypertension and diabetes mellitus, blood pressure, and glucose levels (P=0.003). There were no differences in numbers of endothelial microparticles. Conclusions— The SAs with HF have impaired microvascular and macrovascular endothelial function but preserved arterial elastic properties. Significant ethnic differences in endothelial function are evident in subjects with HF, with ethnicity being associated with microvascular endothelial dysfunction in this disorder.