Monocytes presenting a pro-inflammatory profile persist in patients submitted to a long-term pharmacological treatment after acute myocardial infarction

Abstract

Introduction: Although it is broadly known that monocyte recruitment is involved in atherosclerosis development and that, in accordance with the microenvironment, these cells can be modulated into three well-known subpopulations: Classical (CD14++CD16−), intermediate (CD14++CD16+), and non-classical (CD14+CD16++), the effects of treatment with different pharmacological strategies (based on lipid-lowering and antiplatelets) after acute myocardial infarction upon the monocytes modulation and the role of the chemokine receptors CCR2, CCR5 and CX3CR1 in this context, are poorly understood.Methods: In this study, patients [n = 148, both men (n = 105, 71%) and women (n = 43, 29%)] submitted to treatment with a 2×2 factorial design, in which they received rosuvastatin 20 mg or simvastatin 40 mg plus ezetimibe 10 mg, as well as ticagrelor 90 mg or clopidogrel 75 mg were enrolled. Monocyte subsets were analyzed by flow cytometry at baseline (BL), and after one (1-M) and 6 months (6-M) of treatment.Results: Firstly, our results showed that, regardless of the treatment received, higher percentages of classical monocytes and lower of non-classical monocytes were found at the 6-M time point than BL values, whilst the percentage of intermediate monocytes was higher in all time points assessed than the other subsets. There were reductions in the CCR2 expression by non-classical and intermediate monocytes, without differences for the classical subtype. Concerning the CCR5 expression, there were reductions in the three monocyte subtypes, whereas the CX3CR1 expression increased both in intermediate and classical monocytes, without differences for non-classical monocytes. In relation to the treatment received, a higher percentage of intermediate monocytes at the 6-M time point than the values BL was observed in the group treated with simvastatin + ezetimibe + clopidogrel. No significant differences were found concerning non-classical, intermediate, and classical monocytes, for CCR2, CCR5, and CX3CR1 in the four treatment arms.Conclusion: Taken together, our results demonstrated that even under lipid-lowering and antiplatelet therapy for 6 months, the inflammatory phenotype of monocytes still persisted in the patients enrolled in this study.

Persistence of a proinflammatory status after treatment of the acute myocardial infarction

“…All patients also received therapy with the antiplatelet drugs aspirin + clopidogrel (doses of 300 mg for both medications). The authors found a reduction in the expression of CCR2 in the atorvastatin 80 mg group compared with the 20 mg group after 24 h. On the other hand, in the current study, we found higher expression of CCR2 at mRNA level after treatment, higher levels of intermediate monocytes CCR2+ (the most inflammatory of the three subtypes) and reduction in non-classical monocytes CCR2+ (reparative cells) even after the treatment; these findings confirm the results presented by de Carvalho et al 33 It might suggest a residual inflammatory risk presented by the participants of the study, even under effective lipid-lowering and antiplatelet treatment. This inflammatory risk might be explained by the concept of trained immunity, which refers to a persistence of inflammatory phenotype after months of treatment with lipidlowering, as statins, due to epigenetic reprogramming of histone modifications.…”

“…This inflammatory risk might be explained by the concept of trained immunity, which refers to a persistence of inflammatory phenotype after months of treatment with lipidlowering, as statins, due to epigenetic reprogramming of histone modifications. 33,37,38 Bekkering et al 39 evaluated the effect of 3 months of treatment with statins on monocyte phenotype of patients with familial hypercholesterolemia that were statin-naive, compared with normocholesterolemic participants. The authors showed a trained immune phenotype in monocytes from patients with familial hypercholesterolemia, characterized by an increase in the cytokine production capacity, and proinflammatory transcriptional reprogramming, and a persistent epigenetic changes of histone modifications.…”

“…It might suggest a residual inflammatory risk presented by the participants of the study, even under effective lipid‐lowering and antiplatelet treatment. This inflammatory risk might be explained by the concept of trained immunity, which refers to a persistence of inflammatory phenotype after months of treatment with lipid‐lowering, as statins, due to epigenetic reprogramming of histone modifications 33,37,38 …”

“…At least 10 000 events were acquired. The percentage of cells positive to CCR2, CCR5, and CX3CR1 was evaluated in the three subpopulations of monocytes (classical, intermediate, and non‐classical) 33 …”

“…The percentage of cells positive to CCR2, CCR5, and CX3CR1 was evaluated in the three subpopulations of monocytes (classical, intermediate, and non-classical). 33 Inflammation and myocardial infarction © 2023 Japan Geriatrics Society.…”