Atherosclerosis is characterized by the accumulation of lipids and immune cells, including mast cells and B cells, in the arterial wall. Mast cells contribute to atherosclerotic plaque growth and... Show moreAtherosclerosis is characterized by the accumulation of lipids and immune cells, including mast cells and B cells, in the arterial wall. Mast cells contribute to atherosclerotic plaque growth and destabilization upon active degranulation. The FcεRI-IgE pathway is the most prominent mast cell activation route. Bruton's Tyrosine Kinase (BTK) is involved in FcεRI-signaling and may be a potential therapeutic target to limit mast cell activation in atherosclerosis. Additionally, BTK is crucial in B cell development and B-cell receptor signaling. In this project, we aimed to assess the effects of BTK inhibition on mast cell activation and B cell development in atherosclerosis. In human carotid artery plaques, we showed that BTK is primarily expressed on mast cells, B cells and myeloid cells. In vitro, BTK inhibitor Acalabrutinib dose-dependently inhibited IgE mediated activation of mouse bone marrow derived mast cells. In vivo, male Ldlr-/- mice were fed a high-fat diet for eight weeks, during which mice were treated with Acalabrutinib or control solvent. In Acalabrutinib treated mice, B cell maturation was reduced compared to control mice, showing a shift from follicular II towards follicular I B cells. Mast cell numbers and activation status were not affected. Acalabrutinib treatment did not affect atherosclerotic plaque size or morphology. In advanced atherosclerosis, where mice were first fed a high-fat diet for eight weeks before receiving treatment, similar effects were observed. Conclusively, BTK inhibition by Acalabrutinib alone did neither affect either mast cell activation nor early- and advanced atherosclerosis, despite the effects on follicular B cell maturation. Show less
Skenteris, N.T.; Hemme, E.; Delfos, L.; Karadimou, G.; Karlöf, E.; Lengquist, M.; ... ; Bot, I. Matic, L. 2023
Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing... Show moreCalcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).\nPre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologically validate the contribution of activated and resting MCs in plaques.\nActivated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.\nIntegrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration. Show less
AimsTo evaluate the effect of the ESC/EAS 2019 dyslipidaemia guidelines on patient management of lipid-lowering therapyin patients with acute coronary syndrome (ACS), through a survey designed to... Show moreAimsTo evaluate the effect of the ESC/EAS 2019 dyslipidaemia guidelines on patient management of lipid-lowering therapyin patients with acute coronary syndrome (ACS), through a survey designed to compare post-ACS patient management in 2022 with that in 2018.MethodsOnline questionnaires focused on lipid profile and medications were used to gather data from 2650 ACS patients in 6 European countries, treated between March–June 2022 (ACS EuroPath IV survey). These data were compared with data collected from 2650 patients who participated in the ACS EuroPath I survey (conducted in 2018).ResultsLipid testing was performed in 90% of patients and was done sooner after admission in 2022 versus 2018 (mean 1.4 vs 1.7 days). Increased testing for non-HDL-C, lipoprotein(a), and ApoB was observed over time. At discharge, most patients (≥90%) were receiving lipid-lowering therapy. Prescribing patterns differed, with a higher proportion of patients receiving statin plus ezetimibe combination therapy in 2022 versus 2018 (34% vs 13%). LDL-C levels were lower in 2022 versus 2018 at admission and at 1st, 2nd and 3rd post-discharge follow-up points. More patients achieved low-density lipoprotein cholesterol (LDL-C) goals in 2022 versus 2018 at the first follow-up (average 14 vs 16 weeks since discharge; <70 mg/dL [1.8 mmol/L]: 34% vs 20%; <55 mg/dL [1.4 mmol/L]: 18% vs 10%) and at subsequent follow-up points.ConclusionLDL-C goal achievement has improved since the release of the 2019 guidelines, but lipid management in post-ACS patients remains suboptimal. Show less
Caselli, C.; Giorgi, N. di; Ragusa, R.; Lorenzoni, V.; Smit, J.; Mahdiui, M. el; ... ; SMARTool Investigators 2022
Background and aims: MMP-9 is a predictor of atherosclerotic plaque instability and adverse cardiovascular events, but longitudinal data on the association between MMP9 and coronary disease... Show moreBackground and aims: MMP-9 is a predictor of atherosclerotic plaque instability and adverse cardiovascular events, but longitudinal data on the association between MMP9 and coronary disease progression are lacking. This study is aimed at investigating whether MMP9 is associated with atherosclerotic plaque progression and the related molecular basis in stable patients with chronic coronary syndrome (CCS). Methods: MMP9 serum levels were measured in 157 CCS patients (58 & PLUSMN; 8 years of age; 66% male) undergoing coronary computed tomography angiography at baseline and after a follow up period of 6.5 & PLUSMN; 1.1 years to assess progression of Total, Fibrous, Fibro-fatty, Necrotic Core, and Dense Calcium plaque volumes (PV). Gene expression analysis was evaluated in whole blood using a transcriptomic approach by RNA-seq. Results: At multivariate analysis, serum MMP9 was associated with annual change of Total and Necrotic Core PV (Coefficient 3.205, SE 1.321, P = 0.017; 1.449, SE 0.690, P = 0.038, respectively), while MMP9 gene expression with Necrotic Core PV (Coefficient 70.559, SE 32.629, P = 0.034), independently from traditional cardiovascular risk factors, medications, and presence of obstructive CAD. After transcriptomic analysis, MMP9 expression was linked to expression of genes involved in the innate immunity. Conclusions: Among CCS patients, MMP9 is an independent predictive marker of progression of adverse coronary plaques, possibly reflecting the activity of inflammatory pathways conditioning adverse plaque phenotypes. Thus, blood MMP9 might be used for the identification of patients with residual risk even with optimal man-agement of classical cardiovascular risk factors who may derive the greatest benefit from targeted anti-inflammatory drugs. Show less
Pol, V. van de; Vos, M.; DeRuiter, M.C.; Goumans, M.J.; Vries, C.J.M. de; Kurakula, K. 2020
Despite the advent of new-generation drug-eluting stents, in-stent restenosis remains a significant problem in patients with coronary artery disease. In- stent restenosis is defined as the gradual... Show moreDespite the advent of new-generation drug-eluting stents, in-stent restenosis remains a significant problem in patients with coronary artery disease. In- stent restenosis is defined as the gradual re-narrowing of a stented coronary artery lesion due to arterial damage with subsequent local inflammation of the vessel wall and excessive growth of the vascular smooth muscle cells (vSMCs). Four-and-a-half LIM-domain protein 2 (FHL2) is a scaffold protein involved in regulating vSMC function and inflammation. Previously we have demonstrated that FHL2 prevents vSMC proliferation in a murine carotid artery ligation model. However, the effect of FHL2 on the inflammatory response of the vSMCs is not investigated. Therefore, we studied the inflammatory response in the vessel wall of FHL2-deficient (-KO) mice after carotid artery ligation. We found that circulating cytokines and local macrophage infiltration in the ligated carotid vessels were increased in FHL2-KO mice after carotid artery ligation. Moreover, FHL2-KO vSMCs showed increased secretion of cytokines such as SDF-1 alpha and RANTES, and enhanced activation of the NF kappa B pathway. Finally, we found that blocking the NF kappa B signalling pathway abrogated this pro-inflammatory state in FHL2-KO vSMCs. Taken together, our results demonstrate that FHL2 decreases the inflammatory response of vSMCs through inhibition of the NFkB-signalling pathway. Show less
