Publications by authors named "Anja M van der Laan"

27 Publications

  • Page 1 of 1

Liver X receptors are required for thymic resilience and T cell output.

J Exp Med 2020 10;217(10)

Center for Systems Biology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

The thymus is a primary lymphoid organ necessary for optimal T cell development. Here, we show that liver X receptors (LXRs)-a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity-critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly involuting thymus and acquire a shrunken and prematurely immunoinhibitory peripheral T cell repertoire. LXRαβ's functions are cell specific, and the resulting phenotypes are mutually independent. Although thymic macrophages require LXRαβ for cholesterol efflux, thymic epithelial cells (TECs) use LXRαβ for self-renewal and thymocytes for negative selection. Consequently, TEC-derived LXRαβ protects against homeostatic premature involution and orchestrates thymic regeneration following stress, while thymocyte-derived LXRαβ limits cell disposal during negative selection and confers heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ governs T lymphocyte education and illuminate LXRαβ's indispensable roles in adaptive immunity.
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http://dx.doi.org/10.1084/jem.20200318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537384PMC
October 2020

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses.

J Clin Invest 2019 08 13;129(11):4922-4936. Epub 2019 Aug 13.

Department of Internal Medicine III, University Clinic Halle, Halle, Germany.

T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class-II-restricted epitopes, we found that myosin heavy chain alpha (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in mice. Transferred MYHCA614-629-specific CD4+ T (TCR-M) cells selectively accumulated in the myocardium and mediastinal lymph nodes (med-LN) of infarcted mice, acquired a Treg phenotype with a distinct pro-healing gene expression profile, and mediated cardioprotection. Myocardial Treg cells were also detected in autopsies from patients who suffered a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in MI-patients. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence showing that MI-context induces pro-healing T cell autoimmunity in mice and confirms the existence of an analogous heart/med-LN/T cell axis in MI patients.
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http://dx.doi.org/10.1172/JCI123859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819128PMC
August 2019

Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats.

Basic Res Cardiol 2018 11 12;114(1). Epub 2018 Nov 12.

Department of Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.

Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-α subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-α application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-α changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN-α administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI.
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http://dx.doi.org/10.1007/s00395-018-0709-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244641PMC
November 2018

Sufentanil-medetomidine anaesthesia compared with fentanyl/fluanisone-midazolam is associated with fewer ventricular arrhythmias and death during experimental myocardial infarction in rats and limits infarct size following reperfusion.

Lab Anim 2018 Jun 4;52(3):271-279. Epub 2017 Aug 4.

3 Institute for Cardiovascular Research (ICaR-VU), VU University Medical Centre, Amsterdam, The Netherlands.

To improve infarct healing following myocardial infarction in humans, therapeutic interventions can be applied during the inflammatory response. Animal models are widely used to study this process. However, induction of MI in rodents is associated with high mortality due to ventricular fibrillation (VF) during coronary artery ligation. The anaesthetic agent used during the procedure appears to influence the frequency of this complication. In this retrospective study, the effect on ventricular arrhythmia incidence during ligation and infarct size following in vivo reperfusion of two anaesthetic regimens, sufentanil-medetomidine (SM) and fentanyl/fluanisone-midazolam (FFM) was evaluated in rats. Anaesthetics were administered subcutaneously using fentanyl/fluanisone (0.5 mL/kg) with midazolam (5 mg/kg) (FFM group, n = 48) or sufentanil (0.05 mg/kg) with medetomidine (0.15 mg/kg) (SM group, n = 47). The coronary artery was ligated for 40 min to induce MI. Heart rate and ventricular arrhythmias were recorded during ligation, and infarct size was measured via histochemistry after three days of reperfusion. In the SM group, heart rate and VF incidence were lower throughout the experiment compared with the FFM group (6% versus 30%) ( P < 0.01). Fatal VF did not occur in the SM group whereas this occurred in 25% of the animals in the FFM group. Additionally, after three days of reperfusion, the infarcted area following SM anaesthesia was less than half as large as that following FFM anaesthesia (8.5 ± 6.4% versus 20.7 ± 5.6%) ( P < 0.01). Therefore, to minimize the possibility of complications related to VF and acute death arising during ligation, SM anaesthesia is recommended for experimental MI in rats.
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http://dx.doi.org/10.1177/0023677217724485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967036PMC
June 2018

Monocytic microRNA profile associated with coronary collateral artery function in chronic total occlusion patients.

Sci Rep 2017 05 8;7(1):1532. Epub 2017 May 8.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

An expansive collateral artery network is correlated with improved survival in case of adverse cardiac episodes. We aimed to identify cellular microRNAs (miRNA; miR) important for collateral artery growth. Chronic total occlusion (CTO) patients (n = 26) were dichotomized using pressure-derived collateral flow index (CFI) measurements; high collateral capacity (CFI > 0.39; n = 14) and low collateral (CFI < 0.39; n = 12) capacity. MiRNA profiling via next generation sequencing from various monocyte phenotypes (freshly isolated monocytes, monocytes cultured without stimulant, or stimulation with lipopolysaccharide, interleukin 4, transforming growth factor beta-1, or interferon gamma) revealed significantly different miRNA expression patterns between high versus low collateral capacity patients. Validation by real-time polymerase chain reaction demonstrated significantly decreased expression of miR339-5p in all stimulated monocyte phenotypes of low collateral capacity patients. MiR339-5p showed significant correlation with CFI values in stimulated monocytes. Ingenuity pathway analysis of predicted gene targets of miR339-5p and differential gene expression data from high versus low CFI patients (n = 20), revealed significant association with STAT3 pathway, and also suggested a possible regulatory role for this signaling pathway. These results identify a novel association between miR339-5p and coronary collateral function. Future work examining modulation of miR339-5p and downstream effects on the STAT3 pathway and subsequent collateral vessel growth are warranted.
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http://dx.doi.org/10.1038/s41598-017-01695-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431477PMC
May 2017

Modulators of Macrophage Polarization Influence Healing of the Infarcted Myocardium.

Int J Mol Sci 2015 Dec 10;16(12):29583-91. Epub 2015 Dec 10.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.

To diminish heart failure development after acute myocardial infarction (AMI), several preclinical studies have focused on influencing the inflammatory processes in the healing response post-AMI. The initial purpose of this healing response is to clear cell debris of the injured cardiac tissue and to eventually resolve inflammation and support scar tissue formation. This is a well-balanced reaction. However, excess inflammation can lead to infarct expansion, adverse ventricular remodeling and thereby propagate heart failure development. Different macrophage subtypes are centrally involved in both the promotion and resolution phase of inflammation. Modulation of macrophage subset polarization has been described to greatly affect the quality and outcome of healing after AMI. Therefore, it is of great interest to reveal the process of macrophage polarization to support the development of therapeutic targets. The current review summarizes (pre)clinical studies that demonstrate essential molecules involved in macrophage polarization that can be modulated and influence cardiac healing after AMI.
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http://dx.doi.org/10.3390/ijms161226187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691130PMC
December 2015

Circulating MicroRNAs Characterizing Patients with Insufficient Coronary Collateral Artery Function.

PLoS One 2015 2;10(9):e0137035. Epub 2015 Sep 2.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Background: Coronary collateral arteries function as natural bypasses in the event of coronary obstruction. The degree of collateral network development significantly impacts the outcome of patients after an acute myocardial infarction (AMI). MicroRNAs (miRNAs, miRs) have arisen as biomarkers to identify heterogeneous patients, as well as new therapeutic targets in cardiovascular disease. We sought to identify miRNAs that are differentially expressed in chronic total occlusion (CTO) patients with well or poorly developed collateral arteries.

Methods And Results: Forty-one CTO patients undergoing coronary angiography and invasive assessment of their coronary collateralization were dichotomized based on their collateral flow index (CFI). After miRNA profiling was conducted on aortic plasma, four miRNAs were selected for validation by real-time quantitative reverse transcription polymerase chain reaction in patients with low (CFI<0.39) and high (CFI>0.39) collateral artery capacity. We confirmed significantly elevated levels of miR423-5p (p<0.05), miR10b (p<0.05), miR30d (p<0.05) and miR126 (p<0.001) in patients with insufficient collateral network development. We further demonstrated that each of these miRNAs could serve as circulating biomarkers to discriminate patients with low collateral capacity (p<0.01 for each miRNA). We also determined significantly greater expression of miR30d (p<0.05) and miR126 (p<0.001) in CTO patients relative to healthy controls.

Conclusion: The present study identifies differentially expressed miRNAs in patients with high versus low coronary collateral capacity. We have shown that these miRNAs can function as circulating biomarkers to discriminate between patients with insufficient or sufficient collateralization. This is the first study to identify miRNAs linked to coronary collateral vessel function in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137035PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558025PMC
May 2016

What is the best heparin to treat sepsis with?

Crit Care Med 2015 Jun;43(6):e212-3

Adult Intensive Care Unit, Academic Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1097/CCM.0000000000000916DOI Listing
June 2015

Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells.

Cell Stem Cell 2015 May;16(5):477-87

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. Electronic address:

Following myocardial infarction (MI), myeloid cells derived from the hematopoietic system drive a sharp increase in systemic leukocyte levels that correlates closely with mortality. The origin of these myeloid cells, and the response of hematopoietic stem and progenitor cells (HSPCs) to MI, however, is unclear. Here, we identify a CCR2(+)CD150(+)CD48(-) LSK hematopoietic subset as the most upstream contributor to emergency myelopoiesis after ischemic organ injury. This subset has 4-fold higher proliferation rates than CCR2(-)CD150(+)CD48(-) LSK cells, displays a myeloid differentiation bias, and dominates the migratory HSPC population. We further demonstrate that the myeloid translocation gene 16 (Mtg16) regulates CCR2(+) HSPC emergence. Mtg16(-/-) mice have decreased levels of systemic monocytes and infarct-associated macrophages and display compromised tissue healing and post-MI heart failure. Together, these data provide insights into regulation of emergency hematopoiesis after ischemic injury and identify potential therapeutic targets to modulate leukocyte output after MI.
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http://dx.doi.org/10.1016/j.stem.2015.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426344PMC
May 2015

Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages.

PLoS One 2015 17;10(4):e0124347. Epub 2015 Apr 17.

Dept of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands.

Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR)-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1). In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1) and reduced numbers of CD206-positive (M2) macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401781PMC
April 2016

Long term outcome after mononuclear bone marrow or peripheral blood cells infusion after myocardial infarction.

Heart 2015 Mar 7;101(5):363-8. Epub 2014 Oct 7.

Department of Cardiology, Thorax Center, Erasmus University Medical Center, Rotterdam, The Netherlands.

Objectives: This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65).

Methods: In addition to 3-5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure.

Results: Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9 mL/m(2)) compared with (11.2±19.8 mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2±20.9 mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8±15.0 mL/m(2)) as compared with controls (3.0±16.3 mL/m(2), p=0.07), with again no difference between PBMC (3.3±18.8 mL/m(2)) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67).

Conclusions: Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group.

Trial Registration Number: The Netherlands Trial Register #NTR166 (http://www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).
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http://dx.doi.org/10.1136/heartjnl-2014-305892DOI Listing
March 2015

Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction.

Circ Res 2014 Jul 1;115(2):284-95. Epub 2014 May 1.

From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (T.H., G.C., P.D., H.B.S., M.S., Y.I., Y.S., N.D.S., F.K.S., R.W., M.N.); Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, AL (P.P.); Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.M.v.d.L.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).

Rationale: Macrophages populate the steady-state myocardium. Previously, all macrophages were thought to arise from monocytes; however, it emerged that, in several organs, tissue-resident macrophages may self-maintain through local proliferation.

Objective: Our aim was to study the contribution of monocytes to cardiac-resident macrophages in steady state, after macrophage depletion in CD11b(DTR/+) mice and in myocardial infarction.

Methods And Results: Using in vivo fate mapping and flow cytometry, we estimated that during steady state the heart macrophage population turns over in ≈1 month. To explore the source of cardiac-resident macrophages, we joined the circulation of mice using parabiosis. After 6 weeks, we observed blood monocyte chimerism of 35.3±3.4%, whereas heart macrophages showed a much lower chimerism of 2.7±0.5% (P<0.01). Macrophages self-renewed locally through proliferation: 2.1±0.3% incorporated bromodeoxyuridine 2 hours after a single injection, and 13.7±1.4% heart macrophages stained positive for the cell cycle marker Ki-67. The cells likely participate in defense against infection, because we found them to ingest fluorescently labeled bacteria. In ischemic myocardium, we observed that tissue-resident macrophages died locally, whereas some also migrated to hematopoietic organs. If the steady state was perturbed by coronary ligation or diphtheria toxin-induced macrophage depletion in CD11b(DTR/+) mice, blood monocytes replenished heart macrophages. However, in the chronic phase after myocardial infarction, macrophages residing in the infarct were again independent from the blood monocyte pool, returning to the steady-state situation.

Conclusions: In this study, we show differential contribution of monocytes to heart macrophages during steady state, after macrophage depletion or in the acute and chronic phase after myocardial infarction. We found that macrophages participate in the immunosurveillance of myocardial tissue. These data correspond with previous studies on tissue-resident macrophages and raise important questions on the fate and function of macrophages during the development of heart failure.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.303567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082439PMC
July 2014

Cell therapy in reperfused acute myocardial infarction does not improve the recovery of perfusion in the infarcted myocardium: a cardiac MR imaging study.

Radiology 2014 Jul 8;272(1):113-22. Epub 2014 Mar 8.

From the Department of Cardiology, VU University Medical Center, Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, the Netherlands (L.F.H.J.R., R.N., A.M.B., M.B.M.H., A.C.v.R.); ICIN-Netherlands Heart Institute (ICIN-NHI), Utrecht, the Netherlands (L.F.H.J.R., R.N., A.H., A.M.v.d.L., R.D., P.A.v.d.V.); Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands (A.H., A.M.v.d.L., R.D., J.G.P.T., J.J.P.); Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (P.A.v.d.V., R.A.T.); and Department of Cardiology, Erasmus University Medical Center, Rotterdam, the Netherlands (F.Z.).

Purpose: To investigate the effects of cell therapy on myocardial perfusion recovery after treatment of acute myocardial infarction (MI) with primary percutaneous coronary intervention (PCI).

Materials And Methods: In this HEBE trial substudy, which was approved by the institutional review board (trial registry number ISRCTN95796863), the authors assessed the effects of intracoronary infusion with bone marrow-derived mononuclear cells (BMMCs) or peripheral blood-derived mononuclear cells (PBMCs) on myocardial perfusion recovery by using cardiac magnetic resonance (MR) imaging after revascularization. In 152 patients with acute MI treated with PCI, cardiac MR imaging was performed after obtaining informed consent-before randomization to BMMC, PBMC, or standard therapy (control group)-and repeated at 4-month follow-up. Cardiac MR imaging consisted of cine, rest first-pass perfusion, and late gadolinium enhancement imaging. Perfusion was evaluated semiquantitatively with signal intensity-time curves by calculating the relative upslope (percentage signal intensity change). The relative upslope was calculated for the MI core, adjacent border zone, and remote myocardium. Perfusion differences among treatment groups or between baseline and follow-up were assessed with the Wilcoxon signed rank or Mann-Whitney U test.

Results: At baseline, myocardial perfusion differed between the MI core (median, 6.0%; interquartile range [IQR], 4.1%-8.0%), border zone (median, 8.4%; IQR, 6.4%-10.2%), and remote myocardium (median, 12.2%; IQR, 10.5%-15.9%) (P < .001 for all), with equal distribution among treatment groups. These interregional differences persisted at follow-up (P < .001 for all). No difference in perfusion recovery was found between the three treatment groups for any region.

Conclusion: After revascularization of ST-elevation MI, cell therapy does not augment the recovery of resting perfusion in either the MI core or border zone.
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http://dx.doi.org/10.1148/radiol.14131121DOI Listing
July 2014

Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir.

Eur Heart J 2014 Feb 21;35(6):376-85. Epub 2013 Aug 21.

Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Aims: Monocytes are critical mediators of healing following acute myocardial infarction (AMI), making them an interesting target to improve myocardial repair. The purpose of this study was a gain of insight into the source and recruitment of monocytes following AMI in humans.

Methods And Results: Post-mortem tissue specimens of myocardium, spleen and bone marrow were collected from 28 patients who died at different time points after AMI. Twelve patients who died from other causes served as controls. The presence and localization of monocytes (CD14(+) cells), and their CD14(+)CD16(-) and CD14(+)CD16(+) subsets, were evaluated by immunohistochemical and immunofluorescence analyses. CD14(+) cells localized at distinct regions of the infarcted myocardium in different phases of healing following AMI. In the inflammatory phase after AMI, CD14(+) cells were predominantly located in the infarct border zone, adjacent to cardiomyocytes, and consisted for 85% (78-92%) of CD14(+)CD16(-) cells. In contrast, in the subsequent post-AMI proliferative phase, massive accumulation of CD14(+) cells was observed in the infarct core, containing comparable proportions of both the CD14(+)CD16(-) [60% (31-67%)] and CD14(+)CD16(+) subsets [40% (33-69%)]. Importantly, in AMI patients, of the number of CD14(+) cells was decreased by 39% in the bone marrow and by 58% in the spleen, in comparison with control patients (P = 0.02 and <0.001, respectively).

Conclusions: Overall, this study showed a unique spatiotemporal pattern of monocyte accumulation in the human myocardium following AMI that coincides with a marked depletion of monocytes from the spleen, suggesting that the human spleen contains an important reservoir function for monocytes.
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http://dx.doi.org/10.1093/eurheartj/eht331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916776PMC
February 2014

Myocardial infarct heterogeneity assessment by late gadolinium enhancement cardiovascular magnetic resonance imaging shows predictive value for ventricular arrhythmia development after acute myocardial infarction.

Eur Heart J Cardiovasc Imaging 2013 Dec 13;14(12):1150-8. Epub 2013 Jun 13.

Department of Cardiology, VU University Medical Center, Room ZH 5F012, PO Box 7057, Amsterdam MB 1007, The Netherlands.

Aims: The aim of this study was to assess the association between the proportions of penumbra-visualized by late gadolinium enhanced cardiovascular magnetic resonance imaging (LGE-CMR)-after acute myocardial infarction (AMI) and the prevalence of ventricular tachycardia (VT).

Methods: One-hundred and sixty-two AMI patients, successfully, treated by primary percutaneous coronary intervention (PCI) underwent LGE-CMR after a median of 3 days (3-4) and 24-h Holter monitoring after 1 month. With LGE-CMR, the total amount of enhanced myocardium was quantified and divided into an infarct core (>50% of maximal signal intensity) and penumbra (25-50% of maximal signal intensity). With Holter monitoring, the number of VTs (≥4 successive PVCs) per 24 h was measured.

Results: The mean total enhanced myocardium was 31 ± 11% of the left ventricular mass. The % penumbra accounted for 39 ± 11% of the total enhanced area. In 29 (18%) patients, Holter monitoring showed VT, with a median of 1 episode (1-3) in 24 h. A larger proportion of penumbra within the enhanced area increased the risk of VTs [OR: 1.06 (95% CI: 1.02-1.10), P = 0.003]. After multivariate logistic regression analysis, the presence of ventricular fibrillation before primary PCI [OR: 5.60 (95% CI: 1.54-20.29), P = 0.01] and the proportional amount of penumbra within the enhanced myocardium [OR: 1.06 (95% CI: 1.02-1.10), P = 0.04] were independently associated with VT on Holter monitoring.

Conclusion: Larger proportions of penumbra in the subacute phase after AMI are associated with increased risk of developing VTs. Quantification of penumbra size may become a useful future tool for risk stratification and ultimately for the prevention of ventricular arrhythmias.
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http://dx.doi.org/10.1093/ehjci/jet111DOI Listing
December 2013

Pathological Q waves in myocardial infarction in patients treated by primary PCI.

JACC Cardiovasc Imaging 2013 Mar 20;6(3):324-31. Epub 2013 Feb 20.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objectives: In the present study, we investigated the association of pathological Q waves with infarct size. Furthermore, we investigated whether Q-wave regression was associated with improvement of left ventricular ejection fraction (LVEF), infarct size, and left ventricular dimensions in ST-segment elevation myocardial infarction (STEMI) patients with early Q-wave formation compared with patients without or persistent pathological Q waves.

Background: The criteria for pathological Q waves after acute myocardial infarction (MI) have changed over the years. Also, there are limited data regarding correlation of Q-wave regression and preservation of LVEF in patients with an initial Q-wave MI.

Methods: Standard 12-lead electrocardiograms (ECGs) were recorded in 184 STEMI patients treated with primary percutaneous coronary intervention (PCI). ECGs were recorded before and following PCI, as well as at 1, 4, 12, and 24 months of follow-up. An ECG was scored as Q-wave MI when it showed Q waves in 2 or more contiguous leads according to the 4 readily available clinical definitions used over the years: "classic" criteria, Thrombolysis In Myocardial Infarction criteria, and 2000 and 2007 consensus criteria. Cardiac magnetic resonance (CMR) examination was performed at 4 ± 2 days after reperfusion and repeated after 4 and 24 months. Contrast-enhanced CMR was performed at baseline and 4 months.

Results: The classic ECG criteria showed strongest correlation with infarct size as measured by CMR. The incidence of Q-wave MI according to the classic criteria was 23% 1 h after PCI. At 24 months of follow-up, 40% of patients with initial Q-wave MI displayed Q-wave regression. Patients with a Q-wave MI had larger infarct size and lower LVEF on baseline CMR (24 ± 10% LV mass and 37 ± 8%, respectively) compared with patients with non-Q-wave MI (17 ± 9% LV mass, p < 0.01, and 45 ± 8%, p < 0.001, respectively). Patients with Q-wave regression displayed significantly larger LVEF improvement in 24 months (9 ± 11%) as compared with both persistent Q-wave MI (2 ± 8%) as well as non-Q-wave MI (3 ± 8%, p = 0.04 for both comparisons).

Conclusions: Association of Q waves with infarct size is strongest when using the classic Q-wave criteria. Q-wave regression is associated with the largest improvement of LVEF as assessed with CMR.
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http://dx.doi.org/10.1016/j.jcmg.2012.08.018DOI Listing
March 2013

Republished: healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response.

Postgrad Med J 2013 Jan;89(1047):52-8

Department of Cardiology, Academic Medical Centre, University of Amsterdam, PO Box 22660, Amsterdam 1100 DD, The Netherlands.

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http://dx.doi.org/10.1136/postgradmedj-2012-301623repDOI Listing
January 2013

Left ventricular thrombus formation after acute myocardial infarction as assessed by cardiovascular magnetic resonance imaging.

Eur J Radiol 2012 Dec 17;81(12):3900-4. Epub 2012 Sep 17.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Left ventricular (LV) thrombus formation is a feared complication of myocardial infarction (MI). We assessed the prevalence of LV thrombus in ST-segment elevated MI patients treated with percutaneous coronary intervention (PCI) and compared the diagnostic accuracy of transthoracic echocardiography (TTE) to cardiovascular magnetic resonance imaging (CMR). Also, we evaluated the course of LV thrombi in the modern era of primary PCI.

Methods: 200 patients with primary PCI underwent TTE and CMR, at baseline and at 4 months follow-up. Studies were analyzed by two blinded examiners. Patients were seen at 1, 4, 12, and 24 months for assessment of clinical status and adverse events.

Results: On CMR at baseline, a thrombus was found in 17 of 194 (8.8%) patients. LV thrombus resolution occurred in 15 patients. Two patients had persistence of LV thrombus on follow-up CMR. On CMR at four months, a thrombus was found in an additional 12 patients. In multivariate analysis, thrombus formation on baseline CMR was independently associated with, baseline infarct size (g) (B=0.02, SE=0.02, p<0.001). Routine TTE had a sensitivity of 21-24% and a specificity of 95-98% compared to CMR for the detection of LV thrombi. Intra- and interobserver variation for detection of LV thrombus were lower for CMR (κ=0.91 and κ=0.96) compared to TTE (κ=0.74 and κ=0.53).

Conclusion: LV thrombus still occurs in a substantial amount of patients after PCI-treated MI, especially in larger infarct sizes. Routine TTE had a low sensitivity for the detection of LV thrombi and the interobserver variation of TTE was large.
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http://dx.doi.org/10.1016/j.ejrad.2012.06.029DOI Listing
December 2012

Healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response.

Heart 2012 Sep;98(18):1384-90

Department of Cardiology, Academic Medical Centre, University of Amsterdam, The Netherlands.

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http://dx.doi.org/10.1136/heartjnl-2012-301623DOI Listing
September 2012

Myocardial infarction accelerates atherosclerosis.

Nature 2012 Jul;487(7407):325-9

Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.
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http://dx.doi.org/10.1038/nature11260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326PMC
July 2012

PET/MRI of inflammation in myocardial infarction.

J Am Coll Cardiol 2012 Jan;59(2):153-63

Center for Systems Biology, Massachusetts General Hospital, Boston, USA.

Objectives: The aim of this study was to explore post-myocardial infarction (MI) myocardial inflammation.

Background: Innate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes.

Methods: Acute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose ((18)FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology.

Results: Gd-DTPA-enhanced infarcts showed high (18)FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b(+) cells had 4-fold higher (18)FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 10(4)/mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation.

Conclusions: This study shed light on the innate inflammatory response in remote myocardium after MI.
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http://dx.doi.org/10.1016/j.jacc.2011.08.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257823PMC
January 2012

A proinflammatory monocyte response is associated with myocardial injury and impaired functional outcome in patients with ST-segment elevation myocardial infarction: monocytes and myocardial infarction.

Am Heart J 2012 Jan 23;163(1):57-65.e2. Epub 2011 Nov 23.

Department of Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands.

Background: In patients with ST-segment elevation myocardial infarction (STEMI), the importance of a well-balanced inflammatory reaction has been recognized for years. Monocytes play essential roles in regulating inflammation. Hence, we investigated the association between inflammatory characteristics of monocytes and myocardial injury and functional outcome in patients with STEMI.

Methods: Using flow cytometry, the levels of classical (CD14(++)CD62L(+)) and nonclassical (CD14(+)CD62L(-)) monocytes were analyzed in peripheral blood in 58 patients with STEMI at a median of 5 days (4-6 days) after primary percutaneous coronary intervention. In addition, the monocytic expression of several surface molecules and formation of monocyte-platelet complexes were measured. All patients underwent cardiovascular magnetic resonance imaging at baseline and 4-month follow-up.

Results: At baseline, patients with high levels of classical monocytes had impaired left ventricular (LV) ejection fraction (P = .002), larger infarct size (P = .001), and, often, presence of microvascular obstruction (P = .003). At follow-up, high levels of classical monocytes were negatively associated with the regional systolic LV function independent of the transmural extent of infarction. In contrast, positive associations for the levels of nonclassical monocytes were observed. Finally, up-regulation of macrophage 1 by blood monocytes and increased formation of monocyte-platelet complexes were associated with enhanced myocardial injury at baseline and impaired LV function at follow-up.

Conclusions: This study shows an association between a proinflammatory monocyte response, characterized by high levels of classical monocytes, and severe myocardial injury and poor functional outcome after STEMI. Future studies are required to investigate the biologic nature of this association and therapeutic implications.
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http://dx.doi.org/10.1016/j.ahj.2011.09.002DOI Listing
January 2012

Recovery of microcirculation after intracoronary infusion of bone marrow mononuclear cells or peripheral blood mononuclear cells in patients treated by primary percutaneous coronary intervention the Doppler substudy of the Hebe trial.

JACC Cardiovasc Interv 2011 Aug;4(8):913-20

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Objectives: In the present substudy of the Hebe trial, we investigated the effect of intracoronary bone marrow mononuclear cell (BMMC) and peripheral blood mononuclear cell (PBMC) therapy on the recovery of microcirculation in patients with reperfused ST-segment elevation myocardial infarction (STEMI).

Background: Several studies have suggested that cell therapy enhances neovascularization after STEMI.

Methods: Paired Doppler flow measurements were available for 23 patients in the BMMC group, 18 in the PBMC group, and 19 in the control group. Coronary flow was assessed at 3 to 8 days after primary percutaneous coronary intervention (PCI) and repeated at 4-month follow-up, with intracoronary Doppler flow measurements.

Results: At baseline, the coronary flow velocity reserve was reduced in the infarct-related artery and improved over 4 months in all 3 groups. The increase of coronary flow velocity reserve did not significantly differ between the 2 treatment groups and the control group (BMMC group: 2.0 ± 0.5 to 3.1 ± 0.7; PBMC group: 2.2 ± 0.6 to 3.2 ± 0.8; control group: 2.0 ± 0.5 to 3.4 ± 0.9). Additionally, the decrease in hyperemic microvascular resistance index from baseline to 4-month follow-up was not statistically different between the 2 treatment groups and the control group.

Conclusions: In STEMI patients treated with primary PCI in the Hebe trial, adjuvant therapy with BMMCs or PBMCs does not improve the recovery of microcirculation. Therefore, our data do not support the hypothesis of enhanced neovascularization after this mode of cell therapy. (Multicenter, randomised trial of intracoronary infusion of autologous mononuclear bone marrow cells or peripheral mononuclear blood cells after primary percutaneous coronary intervention [PCI]; ISRCTN95796863).
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http://dx.doi.org/10.1016/j.jcin.2011.05.005DOI Listing
August 2011

Galectin-2 expression is dependent on the rs7291467 polymorphism and acts as an inhibitor of arteriogenesis.

Eur Heart J 2012 May 10;33(9):1076-84. Epub 2011 Aug 10.

Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Aims: In patients with obstructive coronary artery disease (CAD), the growth of collateral arteries, i.e. arteriogenesis, can preserve myocardial tissue perfusion and function. Monocytes modulate this process, supplying locally the necessary growth factors and degrading enzymes. Knowledge on factors involved in human arteriogenesis is scarce. Thus, the aim of the present study is to identify targets in monocytes that are critical for arteriogenesis in patients with CAD.

Methods And Results: A total of 50 patients with a chronic total coronary occlusion were dichotomized according to their collateral flow index. From each patient, RNA was isolated from unstimulated peripheral blood monocytes, monocytes stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, and from macrophages. Increased mRNA expression of galectin-2 was found in three out of four monocytic cell types of patients with a low capacity of the collateral circulation (P= 0.03 for unstimulated monocytes; P= 0.02 for LPS-stimulated monocytes; P= 0.20 for IL-4-stimulated monocytes; P= 0.02 for macrophages). Additionally, galectin-2 mRNA expression was significantly associated with the rs7291467 polymorphism in LGALS2 encoding galectin-2 in all four monocytic cell types. Patient with the rs7291467 CC genotype displayed highest galectin-2 expression, and also tended to have a lower arteriogenic response. To evaluate the effect of galectin-2 on arteriogenesis in vivo, we used a murine hindlimb model. Treatment with galectin-2 markedly impaired the perfusion restoration at Day 7.

Conclusion: Collectively, these results identify galectin-2 as a novel inhibitor of arteriogenesis. Modulation of galectin-2 may constitute a new therapeutic strategy for the stimulation of arteriogenesis in patients with CAD.
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http://dx.doi.org/10.1093/eurheartj/ehr220DOI Listing
May 2012

Expression of a retinoic acid signature in circulating CD34 cells from coronary artery disease patients.

BMC Genomics 2010 Jun 21;11:388. Epub 2010 Jun 21.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat, 1081BT Amsterdam, The Netherlands.

Background: Circulating CD34+ progenitor cells have the potential to differentiate into a variety of cells, including endothelial cells. Knowledge is still scarce about the transcriptional programs used by CD34+ cells from peripheral blood, and how these are affected in coronary artery disease (CAD) patients.

Results: We performed a whole genome transcriptome analysis of CD34+ cells, CD4+ T cells, CD14+ monocytes, and macrophages from 12 patients with CAD and 11 matched controls. CD34+ cells, compared to other mononuclear cells from the same individuals, showed high levels of KRAB box transcription factors, known to be involved in gene silencing. This correlated with high expression levels in CD34+ cells for the progenitor markers HOXA5 and HOXA9, which are known to control expression of KRAB factor genes. The comparison of expression profiles of CD34+ cells from CAD patients and controls revealed a less naïve phenotype in patients' CD34+ cells, with increased expression of genes from the Mitogen Activated Kinase network and a lowered expression of a panel of histone genes, reaching levels comparable to that in more differentiated circulating cells. Furthermore, we observed a reduced expression of several genes involved in CXCR4-signaling and migration to SDF1/CXCL12.

Conclusions: The altered gene expression profile of CD34+ cells in CAD patients was related to activation/differentiation by a retinoic acid-induced differentiation program. These results suggest that circulating CD34+ cells in CAD patients are programmed by retinoic acid, leading to a reduced capacity to migrate to ischemic tissues.
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http://dx.doi.org/10.1186/1471-2164-11-388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901320PMC
June 2010

Targeting angiogenesis to restore the microcirculation after reperfused MI.

Nat Rev Cardiol 2009 Aug 16;6(8):515-23. Epub 2009 Jun 16.

Department of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Since early reperfusion therapy for patients with acute myocardial infarction (AMI) was demonstrated to decrease mortality, numerous improvements in AMI management have focused on prompt reperfusion of the epicardial coronary arteries. However, in a substantial group of patients with AMI, reperfusion of the myocardial tissue is hindered by dysfunction of the microvasculature, despite successful restoration of the epicardial coronary flow. These patients have prolonged ischemia and an adverse clinical outcome. Although several studies investigating the etiology of microvascular dysfunction have been performed, little is known about the restoration process of microvascular dysfunction after reperfused AMI. The objective of this Review is to summarize our knowledge on natural restoration of the microvasculature after reperfused AMI, particularly with regard to angiogenesis, discuss diagnostic modalities used to identify patients with microvascular dysfunction and highlight the potential of pharmacological and cellular interventions to stimulate the recovery of the microvasculature by promoting angiogenesis.
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http://dx.doi.org/10.1038/nrcardio.2009.103DOI Listing
August 2009

Suppression of inflammatory signaling in monocytes from patients with coronary artery disease.

J Mol Cell Cardiol 2009 Feb 14;46(2):177-85. Epub 2008 Nov 14.

Department of Cardiology, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.

Monocytes and T-cells play an important role in the development of atherosclerotic coronary artery disease (CAD). Transcriptome analysis of circulating mononuclear cells from carefully matched atherosclerotic and control patients will potentially provide insights into the pathophysiology of atherosclerosis and supply biomarkers for diagnostic purposes. From patients undergoing coronary angiography because of anginal symptoms, we carefully matched 18 patients with severe triple-vessel CAD to 13 control patients without angiographic signs of CAD. All patients were on statin and aspirin treatment. Elevated soluble-ICAM levels demonstrated increased vascular inflammation in atherosclerotic patients. RNA from circulating CD4+ T-cells, CD14+ monocytes, lipopolysaccharide-stimulated monocytes, and macrophages was subjected to genome-wide expression analysis. In CD14+ monocytes, few inflammatory genes were overexpressed in control patients, while atherosclerotic patients showed overexpression of a group of Krüppel-associated box - containing transcription factors involved in negative regulation of gene expression. These differences disappeared upon LPS-stimulation or differentiation towards macrophages. No consistent changes in T cell transcriptomes were detected. Large inter-individual variability prevented the use of single differentially expressed genes as biomarkers, while monocyte gene expression signature predicted patient status with an accuracy of 84%. In this comprehensive analysis of circulating cell transcriptomes in atherosclerotic CAD, cautious patient matching revealed only small differences in transcriptional activity in different mononuclear cell types. Only an indication of a negative feedback to inflammatory gene expression was detected in atherosclerotic patients. Transcriptome differences of circulating cells possibly play less of a role than hitherto thought in the individual patient's susceptibility to atherosclerotic CAD, when appropriately matched for clinical symptoms and medication taken.
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http://dx.doi.org/10.1016/j.yjmcc.2008.10.029DOI Listing
February 2009