A Novel Monocyte Subset as a Unique Signature of Atherosclerotic Plaque Rupture (original) (raw)
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Scientific Reports
The prevalence of a macrophage phenotype in atherosclerotic plaque may drive its progression and/or instability. Macrophages from coronary plaques are not available, and monocyte-derived macrophages (MDMs) are usually considered as a surrogate. We compared the MDM profile obtained from coronary artery disease (CAD) patients and healthy subjects, and we evaluated the association between CAD MDM profile and in vivo coronary plaque characteristics assessed by optical coherence tomography (OCT). At morphological analysis, MDMs of CAD patients had a higher prevalence of round than spindle cells, whereas in healthy subjects the prevalence of the two morphotypes was similar. Compared to healthy subjects, MDMs of CAD patients had reduced efferocytosis, lower transglutaminase-2, CD206 and CD163 receptor levels, and higher tissue factor (TF) levels. At OCT, patients with a higher prevalence of round MDMs showed more frequently a lipid-rich plaque, a thin-cap fibroatheroma, a greater intraplaque macrophage accumulation, and a ruptured plaque. The MDM efferocytosis correlated with minimal lumen area, and TF levels in MDMs correlated with the presence of ruptured plaque. MDMs obtained from CAD patients are characterized by a morpho-phenotypic heterogeneity with a prevalence of round cells, showing pro-inflammatory and pro-thrombotic properties. The MDM profile allows identifying CAD patients at high risk. Macrophages are heterogeneous in morphology and in function, and this heterogeneity has been well documented in different physiological and pathological conditions 1-3. Also in experimental models and human atherosclerotic lesions, macrophages display morpho-phenotypic heterogeneity, with distinct subpopulations showing pro-inflammatory or reparative properties 1,4-7. On these premises, it has been hypothesized that the prevalence of a specific macrophage phenotype may exert harmful or beneficial functions in the progression and/or destabilization of the atherosclerotic plaque 8,9. We have previously reported that monocytes isolated from healthy subjects and spontaneously differentiated into macrophages (MDMs) give rise to two dominant morphotypes coexisting in the same culture, namely round MDMs showing a non-inflammatory and reparative phenotype, and spindle MDMs exhibiting a pro-inflammatory profile 10. To date, no information is available concerning the behavior of MDMs in patients with coronary artery disease (CAD). Therefore, an insight into the signature of MDMs obtained from patients with established CAD and their potential association with in vivo coronary plaque features might be of help in the understanding of the pro/anti-atherogenic potential of these cells. Optical coherence tomography (OCT) provides high-resolution (10 µm) in vivo images of the atherosclerotic plaque, allowing to acquire detailed information about its morphology and composition, including fibrous 1 centro cardiologico Monzino i.R.c.c.S., Milan, italy.
Scandinavian Journal of Immunology, 2015
The inflammation underlying both atherosclerosis and acute coronary syndromes is strongly related to monocyte-related actions. However, different monocyte subsets can play differential roles in the formation and destabilization of atherosclerotic plaque as well as healing of damaged myocardial tissue. Monocytes are currently being divided into three functionally distinct subsets with different levels of CD14 (cluster of differentiation 14) and CD16 expression. Thus, there are classical CD14++CD16-, intermediate CD14++CD16+ and nonclassical CD14+CD16++ monocytes. Here, we summarize the current knowledge on complex activities of different monocyte subsets in atherosclerosis and acute coronary syndromes. Moreover, we discuss which monocyte subsets can serve either as predictive biomarkers of cardiovascular risk or as potential targets used in atherosclerosis and its complications.
Atherosclerosis, 2010
The aim of the present study was to examine the relation between monocyte subsets and the presence, extent, and vulnerability characteristics of non-calcified coronary plaques (NCPs) as assessed by multidetector computed tomography (MDCT). Methods: We studied 73 patients with stable angina pectoris who underwent MDCT. Two monocyte subsets (CD14 + CD16 − and CD14 + CD16 +) were measured by flow cytometry. Coronary artery plaques were assessed by 64-slice MDCT. We defined NCP vulnerability according to the presence of positive remodeling (remodeling index > 1.05) and/or low CT attenuation plaques (<35 HU). Results: A total of 40 (55%) patients had identifiable vulnerable plaques. The relative proportion of CD14 + CD16 + monocytes was significantly greater in patients with 1 or multiple vulnerable plaques than in patients with no vulnerable plaques or control (healthy) subjects. In addition, the relative proportion of CD14 + CD16 + monocytes was positively correlated with remodeling index (r = 0.40, P < 0.01) and negatively correlated with CT attenuation value (r = −0.34, P < 0.01). Conclusion: The present results suggest that an increased subset of CD14 + CD16 + monocytes is related to coronary plaque vulnerability in patients with stable angina pectoris.
Monocyte and Macrophage Subtypes as Paired Cell Biomarkers for Coronary Artery Disease
Journal of the American College of Cardiology, 2018
Background: Monocytes and macrophages are central to atherosclerosis, but how they mark progression of human coronary artery disease (CAD) is unclear. We tested whether patients' monocyte subtypes paired with their derived macrophage profiles correlate with extent of CAD. Methods: Peripheral blood was collected from 30 patients undergoing cardiac catheterization, and patients were categorized as having no significant CAD, single vessel disease, or multivessel disease according to the number of affected coronary arteries. Mononuclear cells were measured for monocyte markers CD14 and CD16 by flow cytometry, and separate monocytes were cultured into macrophages over 7 days and measured for polarization markers CD86 and CD206. Results: At baseline, patients with greater CAD burden were older with higher rates of statin use, whereas all other characteristics were similar across the spectrum of coronary disease. Non-classical (CD14 lo CD16 hi) and all CD16 + monocytes were elevated in patients with single vessel and multivessel disease compared to those without significant CAD (8.6% and 10.5% vs. 2.8%, p < 0.05), whereas regulatory M2 macrophages (CD206 +) were decreased in patients with single vessel and multivessel disease (0.34% and 0.34% vs. 1.4%, p < 0.05). An inverse relationship between paired CD16 + monocytes and M2 macrophages marked CAD severity. CAD was also found to be more tightly associated with CD16 + cells than age or traditional cardiovascular risk factors on multiple regression analysis of these patients. Conclusions: CAD extent is correlated directly with CD16 + monocytes and inversely with M2 (CD206 +) macrophages, suggesting circulating monocytes may influence downstream polarization of lesional macrophages. These measures of monocyte and macrophage subtypes hold potential as biomarkers in CAD. .
Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture
Circulation, 1994
BACKGROUND Rupture of atherosclerotic plaques is probably the most important mechanism underlying the sudden onset of acute coronary syndromes. Macrophages may release lytic enzymes that degrade the fibrous cap and therefore produce rupture of the atherosclerotic plaque. This study was designed to quantify macrophage content in coronary plaque tissue from patients with stable and unstable coronary syndromes. METHODS AND RESULTS Hematoxylin and eosin and immunostaining with anti-human macrophage monoclonal antibody (PG-M1) were performed. Computerized planimetry was used to analyze 26 atherectomy specimens comprising 524 pieces of tissue from 8 patients with chronic stable angina, 8 patients with unstable angina, and 10 patients with non-Q-wave myocardial infarction. Total plaque area was 417 +/- 87 mm2 x 10(-2) in patients with stable angina, 601 +/- 157 mm2 x 10(-2) in patients with unstable angina, and 499 +/- 87 mm2 x 10(-2) in patients with non-Q-wave myocardial infarction (P = ...
Monocyte Count Is a Predictor of Novel Plaque Formation
Stroke, 2005
Background and Purpose— Activation of monocytes and differentiation into lipid-laden macrophages are fundamental events in generation of atherosclerotic lesions. There exist few data on monocyte activity and the risk for atherosclerosis. In this prospective population-based study, we examined whether monocyte count in blood is a predictor of future plaque formation in persons without pre-existing carotid atherosclerosis. Methods— At baseline, we measured monocyte count, white cell count (WCC), fibrinogen, intima-media thickness (IMT), and traditional cardiovascular risk factors in 2610 men and women aged 25 to 82 years who on ultrasound had no plaque in their right carotid artery. After 7 years of follow-up, a new ultrasound screening was performed and the number of novel plaques was grouped as none, 1 plaque, and 2 or more plaques. Results— In multivariate analysis, monocyte count, age, sex, total cholesterol, current smoking, systolic blood pressure, and IMT were independent predi...
Journal of the American College of Cardiology, 2004
This study was designed to utilize optical coherence tomography (OCT) images of coronary atherosclerotic plaque macrophages to investigate the relationship between macrophage distributions and clinical syndrome. BACKGROUND The relative significance of focal macrophage infiltration and generalized coronary inflammation for predicting acute coronary events is a currently a source of considerable controversy in cardiology. Lack of a high-resolution cross-sectional imaging modality has limited macrophage evaluation in vivo.
Cytometry. Part A : the journal of the International Society for Analytical Cytology, 2017
This study was performed to gain further insight in the heterogeneity of monocytes in the different categories of acute coronary syndrome (ACS), especially between patients with unstable angina pectoris, ST-elevation myocardial infarction (STEMI), and non-ST-elevation myocardial infarction (NSTEMI). For this purpose, blood samples were collected in the acute phase from patients presenting with an ACS. These samples were examined with multiparameter flow cytometry to identify the different monocyte subsets and to analyze the expression of monocyte-associated molecules. Leukocytes, as well as an absolute number of monocytes, showed a clear and significant increase in patients with STEMI. This increase was seen in all subtypes of monocytes. The classical monocytes (CD14++CD16-) of patients with an NSTEMI had a significantly increased CD11b expression when compared to the control group, while these cells showed a decreased expression pattern in STEMI patients. This increased CD11b-expre...
Circulation Journal, 2012
Background: Circulating monocytes can be divided into 2 subsets typically identified by the expression of CD14 and CD16. Although previous studies have shown that circulating monocytes contribute to the progression of coronary atherosclerotic lesions, the relationship between the severity of coronary artery disease (CAD) and the 2 distinct monocyte subsets has not previously been evaluated. We investigated the relationship between the monocyte subsets and the severity of CAD assessed by coronary angiography (CAG) in patients with stable angina pectoris (SAP). Methods and Results: We enrolled 125 patients who underwent diagnostic CAG. Patients were divided into 3 groups: those without CAD, those with single-vessel disease (SVD), and those with multiple-vessel disease (MVD). In addition, the severity of CAD was evaluated by Gensini score. The 2 monocyte subsets (CD14 + CD16and CD14 + CD16 +) were measured by flow cytometry. Circulating CD14 + CD16 + monocytes were more frequently observed in patients with MVD than in those with SVD or without CAD. The proportion of CD14 + CD16 + monocytes positively correlated with Gensini score (r=0.618, P<0.001). Multivariate logistic regression analysis revealed that the proportion of CD14 + CD16 + monocytes was an independent contributor to MVD (odds ratio: 1.475; 95% confidence interval: 1.273-1.708, P<0.001). Conclusions: A preferential increase in peripheral CD14 + CD16 + monocytes may be closely related to the severity of CAD in patients with SAP.