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After myocardial infarction (MI), emergency hematopoiesis produces inflammatory myeloid cells that accelerate atherosclerosis and promote heart failure. Since the balance between glycolysis and mitochondrial metabolism regulates hematopoietic stem cell homeostasis, metabolic cues may influence emergency myelopoiesis. Here, we show in humans and female mice that hematopoietic progenitor cells increase fatty acid metabolism after MI. Blockade of fatty acid oxidation by deleting carnitine palmitoyltransferase ( Cpt1A ) in hematopoietic cells of Vav1 Cre/+ Cpt1A fl/fl mice limited hematopoietic progenitor proliferation and myeloid cell expansion after MI. We also observed reduced bone marrow adiposity in humans, pigs and mice following MI. Inhibiting lipolysis in adipocytes using Adipoq CreERT2 Atgl fl/fl mice or local depletion of bone marrow adipocytes in Adipoq CreERT 2iDTR mice also curbed emergency hematopoiesis. Furthermore, systemic and regional sympathectomy prevented bone marrow adipocyte shrinkage after MI. These data establish a critical role for fatty acid metabolism in post-MI emergency hematopoiesis., Competing Interests: Competing interests statement All other authors declare no conflicts of interest, financial or otherwise.

Cardiac magnetic resonance (CMR) imaging is a valuable noninvasive tool for evaluating tissue response following catheter ablation of atrial tissue. This review provides an overview of the contemporary CMR strategies to visualize atrial ablation lesions in both the acute and chronic postablation stages, focusing on their strengths and limitations. Moreover, the accuracy of CMR imaging in comparison to atrial lesion histology is discussed. T2-weighted CMR imaging is sensitive to edema and tends to overestimate lesion size in the acute stage after ablation. Noncontrast agent-enhanced T1-weighted CMR imaging has the potential to provide more accurate assessment of lesions in the acute stage but may not be as effective in the chronic stage. Late gadolinium enhancement imaging can be used to detect chronic atrial scarring, which may inform repeat ablation strategies. Moreover, novel imaging strategies are being developed, but their efficacy in characterizing atrial lesions is yet to be determined. Overall, CMR imaging has the potential to provide virtual histology that aids in evaluating the efficacy and safety of catheter ablation and monitoring of postprocedural myocardial changes. However, technical factors, scanning during arrhythmia, and transmurality assessment pose challenges. Therefore, further research is needed to develop CMR strategies to visualize the ablation lesion maturation process more effectively., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Purpose: Left atrial (LA) sphericity is a novel, geometry-based parameter that has been used to visualize and quantify LA geometrical remodeling in patients with atrial fibrillation (AF). This study examined the association between LA sphericity, and LA longitudinal strain and strain rate measured by feature-tracking in AF patients., Methods: 128 AF patients who underwent cardiovascular magnetic resonance (CMR) imaging in sinus rhythm prior to their pulmonary vein isolation (PVI) procedure were retrospectively analyzed. LA sphericity was calculated by segmenting the LA (excluding the pulmonary veins and the LA appendage) on a 3D contrast enhanced MR angiogram and comparing the resulting shape with a perfect sphere. LA global reservoir strain, conduit strain, contractile strain and corresponding strain rates were derived from cine images using feature-tracking. For statistical analysis, Pearson correlations, multivariable logistic regression analysis, and Student t-tests were used., Results: Patients with a spherical LA (dichotomized by the median value) had a lower reservoir strain and conduit strain compared to patients with a non-spherical LA (-15.4 ± 4.2% vs. -17.1 ± 3.5%, P = 0.02 and - 8.2 ± 3.0% vs. -9.5 ± 2.6%, P = 0.01, respectively). LA strain rate during early ventricular diastole was also different between both groups (-0.7 ± 0.3s - 1 vs. -0.9 ± 0.3s - 1 , P = 0.001). In contrast, no difference was found for LA contractile strain (-7.2 ± 2.6% vs. -7.6 ± 2.2%, P = 0.30)., Conclusions: LA passive strain is significantly impaired in AF patients with a spherical LA, though this relation was not independent from LA volume., (© 2023. The Author(s).)

Purpose: The present study assesses different left atrial (LA) strain approaches in relation to atrial fibrillation (AF) recurrence after ablation and compares LA feature tracking (FT) strain to novel rapid LA strain approaches in AF patients., Methods: This retrospective single-center study comprised of 110 prospectively recruited AF patients who underwent cardiac magnetic resonance (CMR) imaging in sinus rhythm prior to their first pulmonary vein isolation ablation. LA rapid strain (long axis strain and atrioventricular (AV)-junction strain), LA FT strain, and LA volumes were derived from 2-chamber and 4-chamber cine images. AF recurrence was followed up for 12 months using either 12‑lead ECGs or rhythm Holter monitoring., Results: Arrhythmia recurrence was observed in 39 patients (36%) after the 90-day blanking period, occurring at a median of 181 (122-286) days. LA long axis strain, AV-junction strain, and FT strain were all more impaired in patients with AF recurrence compared to patients without AF recurrence (long axis strain: P < 0.01; AV-junction strain: P < 0.001; FT strain: P < 0.01, respectively). Area under the curve (AUC) values for LA remodeling parameters in association with AF recurrence were 0.68 for long axis strain, 0.68 for AV-junction strain, 0.66 for FT strain, 0.66 for LA volume index. Phasic FT LA strain demonstrated that contractile strain had the highest AUC (0.70)., Conclusion: Both LA rapid strain and LA FT strain are associated with arrhythmia recurrence after ablation in AF patients. LA rapid strain can be a convenient and reproducible alternative for LA FT strain to assess LA function in clinical practice., Competing Interests: Declaration of Competing Interest Authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Bi-atrial remodelling in patients with atrial fibrillation (AF) is rarely assessed and data on the presence of right atrial (RA) fibrosis, the relationship between RA and left atrial (LA) fibrosis, and possible association of RA remodelling with AF recurrence after ablation in patients with AF is limited., Methods and Results: A total of 110 patients with AF undergoing initial pulmonary vein isolation (PVI) were included in the present study. All patients were in sinus rhythm during cardiac magnetic resonance (CMR) imaging performed prior to ablation. LA and RA volumes and function (volumetric and feature tracking strain) were derived from cine CMR images. The extent of LA and RA fibrosis was assessed from 3D late gadolinium enhancement images. AF recurrence was followed up for 12 months after PVI using either 12-lead electrocardiograms or Holter monitoring. Arrhythmia recurrence was observed in 39 patients (36%) after the 90-day blanking period, occurring at a median of 181 (interquartile range: 122-286) days. RA remodelling parameters were not significantly different between patients with and without AF recurrence after ablation, whereas LA remodelling parameters were different (volume, emptying fraction, and strain indices). LA fibrosis had a strong correlation with RA fibrosis (r = 0.88, P < 0.001). Both LA and RA fibrosis were not different between patients with and without AF recurrence., Conclusions: This study shows that RA remodelling parameters were not predictive of AF recurrence after AF ablation. Bi-atrial fibrotic remodelling is present in patients with AF and moreover, the amount of LA fibrosis had a strong correlation with the amount of RA fibrosis., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Abnormal hematopoiesis advances cardiovascular disease by generating excess inflammatory leukocytes that attack the arteries and the heart. The bone marrow niche regulates hematopoietic stem cell proliferation and hence the systemic leukocyte pool, but whether cardiovascular disease affects the hematopoietic organ's microvasculature is unknown. Here we show that hypertension, atherosclerosis and myocardial infarction (MI) instigate endothelial dysfunction, leakage, vascular fibrosis and angiogenesis in the bone marrow, altogether leading to overproduction of inflammatory myeloid cells and systemic leukocytosis. Limiting angiogenesis with endothelial deletion of Vegfr2 (encoding vascular endothelial growth factor (VEGF) receptor 2) curbed emergency hematopoiesis after MI. We noted that bone marrow endothelial cells assumed inflammatory transcriptional phenotypes in all examined stages of cardiovascular disease. Endothelial deletion of Il6 or Vcan (encoding versican), genes shown to be highly expressed in mice with atherosclerosis or MI, reduced hematopoiesis and systemic myeloid cell numbers in these conditions. Our findings establish that cardiovascular disease remodels the vascular bone marrow niche, stimulating hematopoiesis and production of inflammatory leukocytes.

Background: Atrial fibrillation (AF) is associated with profound structural and functional changes in the atria. In the present study, we investigated the association between left atrial (LA) phasic function and the extent of LA fibrosis using advanced cardiovascular magnetic resonance (CMR) imaging techniques, including 3-dimensional (3D) late gadolinium enhancement (LGE) and feature tracking., Methods: Patients with paroxysmal and persistent AF (n = 105) underwent CMR in sinus rhythm. LA global reservoir strain, conduit strain and contractile strain were derived from cine CMR images using CMR feature tracking. The extent of LA fibrosis was assessed from 3D LGE images. Healthy subjects underwent CMR and served as controls (n = 19)., Results: Significantly lower LA reservoir strain, conduit strain and contractile strain were found in AF patients, as compared to healthy controls (- 15.9 ± 3.8% vs. - 21.1 ± 3.6% P < 0.001, - 8.7 ± 2.7% vs. - 12.6 ± 2.5% P < 0.001 and - 7.2 ± 2.3% vs. - 8.6 ± 2.2% P = 0.02, respectively). Patients with a high degree of LA fibrosis (dichotomized by the median value) had lower reservoir strain and conduit strain compared to patients with a low degree of LA fibrosis (- 15.0 ± 3.9% vs. - 16.9 ± 3.3%, P = 0.02 and - 7.9 ± 2.7% vs. - 9.5 ± 2.6%, P = 0.01, respectively). In contrast, no difference was found for LA contractile strain (- 7.1 ± 2.4% vs. - 7.4 ± 2.3%, P = 0.55)., Conclusions: Impaired LA reservoir and conduit strain are present in AF patients with extensive atrial fibrosis. Future studies are needed to examine the biologic nature of this association and possible therapeutic implications., (© 2021. The Author(s).)

Hypoxia-inducible factors (HIFs) are activated in parenchymal cells in response to low oxygen and as such have been proposed as therapeutic targets during hypoxic insult, including myocardial infarction (MI). HIFs are also activated within macrophages, which orchestrate the tissue repair response. Although isoform-specific therapeutics are in development for cardiac ischemic injury, surprisingly, the unique role of myeloid HIFs, and particularly HIF-2α, is unknown. Using a murine model of myocardial infarction and mice with conditional genetic loss and gain of function, we uncovered unique proinflammatory roles for myeloid cell expression of HIF-1α and HIF-2α during MI. We found that HIF-2α suppressed anti-inflammatory macrophage mitochondrial metabolism, while HIF-1α promoted cleavage of cardioprotective MerTK through glycolytic reprogramming of macrophages. Unexpectedly, combinatorial loss of both myeloid HIF-1α and HIF-2α was catastrophic and led to macrophage necroptosis, impaired fibrogenesis, and cardiac rupture. These findings support a strategy for selective inhibition of macrophage HIF isoforms and promotion of anti-inflammatory mitochondrial metabolism during ischemic tissue repair., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 DeBerge et al.)

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., Competing Interests: Disclosures: M. Nahrendorf received consulting fees from Verseau Therapeutics, Gimv, and IFM Therapeutics. A. Tall reported personal fees from Amgen, personal fees from CSL, personal fees from Astra Zeneca, personal fees from Janssen, other from Fortico Biotech, other from Staten Biotech, and personal fees from The Medicines Company outside the submitted work. F. Swirski reported personal fees from Verseau Therapeutics outside the submitted work. No other disclosures were reported., (© 2020 Chan et al.)

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.

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.

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.

Background: In this study, two assumptions derived from the Good Lives Model were examined: whether subjective Quality of Life is related to delinquent behaviour and psychosocial problems, and whether adolescents with adequate coping skills are less likely to commit delinquent behaviour or show psychosocial problems., Method: To this end, data of 95 adolescents with severe psychiatric problems who participated in a four-wave longitudinal study were examined. Subjective Quality of Life was assessed with the ten domains of the Lancashire Quality of Life Profile and coping skills with the Utrecht Coping List for Adolescents., Results: Results showed that adolescents who reported a lower Quality of Life on the health domain had more psychosocial problems at follow-up. No relationship was found between Quality of Life and delinquent behaviour. In addition, active and passive coping were associated with delinquent behaviour and psychosocial functioning at follow-up., Conclusions: Based on the results of this longitudinal study, the strongest support was found for the second assumption derived from the Good Lives Model. Adolescents with adequate coping skills are less likely to commit delinquent behaviour and have fewer psychosocial problems at follow-up. The current study provides support for the use of strength-based elements in the treatment programmes for adolescents in secure residential care.

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 p ) measurements; high collateral capacity (CFI p  > 0.39; n = 14) and low collateral (CFI p  < 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 p values in stimulated monocytes. Ingenuity pathway analysis of predicted gene targets of miR339-5p and differential gene expression data from high versus low CFI p 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.

This study investigated the longitudinal relation between general well-being and self-esteem of male adolescents with severe psychiatric disorders. Moreover, the transition out of secure residential care was studied. Adolescents ( N = 172) were assessed three times with 6 months between each assessment. The sample comprised adolescents who were admitted throughout the entire study ( n = 116) and who had been discharged at 6/12 months follow-up ( n = 56). General well-being and self-esteem were stable concepts over time. The relation between general well-being and self-esteem differed for both groups. Among the admitted group general well-being positively predicted self-esteem and self-esteem negatively predicted general well-being from Time 2 to Time 3. Among the discharged adolescents, self-esteem at Time 1 positively predicted general well-being at Time 2 and general well-being at Time 2 positively predicted self-esteem at Time 3. Changing social contexts, as well as problems experienced during the transition out of secure care, might affect this relationship.

Many variant proteins encoded by Plasmodium-specific multigene families are exported into red blood cells (RBC). P. falciparum-specific variant proteins encoded by the var, stevor and rifin multigene families are exported onto the surface of infected red blood cells (iRBC) and mediate interactions between iRBC and host cells resulting in tissue sequestration and rosetting. However, the precise function of most other Plasmodium multigene families encoding exported proteins is unknown. To understand the role of RBC-exported proteins of rodent malaria parasites (RMP) we analysed the expression and cellular location by fluorescent-tagging of members of the pir, fam-a and fam-b multigene families. Furthermore, we performed phylogenetic analyses of the fam-a and fam-b multigene families, which indicate that both families have a history of functional differentiation unique to RMP. We demonstrate for all three families that expression of family members in iRBC is not mutually exclusive. Most tagged proteins were transported into the iRBC cytoplasm but not onto the iRBC plasma membrane, indicating that they are unlikely to play a direct role in iRBC-host cell interactions. Unexpectedly, most family members are also expressed during the liver stage, where they are transported into the parasitophorous vacuole. This suggests that these protein families promote parasite development in both the liver and blood, either by supporting parasite development within hepatocytes and erythrocytes and/or by manipulating the host immune response. Indeed, in the case of Fam-A, which have a steroidogenic acute regulatory-related lipid transfer (START) domain, we found that several family members can transfer phosphatidylcholine in vitro. These observations indicate that these proteins may transport (host) phosphatidylcholine for membrane synthesis. This is the first demonstration of a biological function of any exported variant protein family of rodent malaria parasites., Competing Interests: The authors have declared that no competing interests exist.

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.

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.

Coping, general well-being and self-esteem play an important role during the process of adaptation to turning points in life-course. This study aimed to investigate the effect of coping on both the development of general well-being and self-esteem of adolescents with severe psychiatric problems in secure residential care. In addition, risk and protective factors were taken into account. Adolescents between the age of 16 and 18 (N = 172) were followed for 1.5 years. General well-being and self-esteem were assessed with the Lancashire Quality of Life Profile and the Self-Perception Profile for Adolescents, respectively. In addition, the Utrecht Coping List for Adolescents and the Structured Assessment of Violence Risk in Youth were administered. Results showed that the longitudinal relation between general well-being and self-esteem is no longer significant after adding active and passive coping to the model. The use of active coping strategies was associated with a higher self-esteem. The use of passive coping strategies was associated with a lower self-esteem and also a lower perceived general well-being. Having multiple risks in the individual and/or social/contextual domain affected the developmental pattern of general well-being. During treatment of adolescents with severe psychiatric problems in secure residential care, attention should be paid for enhancing those capabilities and skills, like coping, which help adolescents to fulfill their needs and consequently enhance their well-being. Enhancing the well-being of adolescents might in the long run decrease the chance of reoffending and/or psychiatric relapse.

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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., (© 2014 American Heart Association, Inc.)

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., (© RSNA, 2014.)

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.

Dupuytren's disease (DD) is a benign fibroproliferative disease of the hand. It is characterized by the excessive production of extracellular matrix (ECM) proteins, which form a strong fibrous tissue between the handpalm and fingers, permanently disrupting the fine movement ability. The major contractile element in DD is the myofibroblast (MFB). This cell has both fibroblast and smooth muscle cell-type characteristics and causes pathological collagen deposition. MFBs generate contractile forces that are transmitted to the surrounding collagen matrix. Μajor profibrotic factors are members of the transforming growth factor-β (TGFβ) pathway which directly regulate the expression levels of several fibrous proteins such as collagen type 1, type 3, and α-smooth muscle actin. Molecular modulation of this signaling pathway could serve as a therapeutic approach. We, therefore, have developed an ex vivo "clinical trial" system to study the properties of intact, patient-derived resection specimens. In these culture conditions, Dupuytren's tissue retains its three-dimensional (3D) structure and viability. As a novel antifibrotic therapeutic approach, we targeted TGFβ type 1 receptor (also termed activin receptor-like kinase 5) expression in cultured Dupuytren's specimens by antisense oligonucleotide-mediated exon skipping. Antisense oligonucleotides targeting activin receptor-like kinase 5 showed specific reduction of ECM and potential for clinical application.Molecular Therapy-Nucleic Acids (2014) 3, e142; doi:10.1038/mtna.2013.69; published online 21 January 2014.

Inadequate healing following acute myocardial infarction (AMI) can lead to the development of heart failure. The ischemic myocardium triggers an inflammatory response that clears cell debris and initiates the onset of scar tissue formation. The duration and intensity of this inflammatory response have been linked to the cardiac functioning post-AMI. In order to diminish scar tissue formation and stimulate regeneration of cardiac tissue, mesenchymal stem cell (MSC) have been applied post-AMI and showed beneficial effects on cardiac function. However, other than the expected regeneration of cardiac tissue, modulation of the inflammatory response post-AMI, especially related to an effect on monocytes/macrophages, was recently found to be an important aspect of MSC therapy. In healing post-AMI, monocytes and macrophages are key players that can either stimulate or repress inflammation using different phenotypes. Increased levels of the proinflammatory phenotype have clinically been associated with poor cardiac functional outcome post-AMI. MSC have been suggested to switch the monocytes/macrophages phenotype into a more anti-inflammatory state and might therefore beneficially influence the duration and intensity of the inflammatory response and subsequent cardiac function post-AMI. To gain more insight into this effect of MSC, this review provides an overview of the most relevant studies regarding this modulatory effect of MSC on monocytes/macrophages including its mechanisms to improve cardiac functioning post-AMI.

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.

Objective: Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis., Design: Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI)., Patients: Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed., Interventions: Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure., Results: The mean CFI was 0.39 ± 0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=-0.01, SE=0.005, p=0.03, B=-0.04, SE=0.02, p=0.03 and B=-0.002, SE=0.001, p=0.011)., Conclusions: In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD.

This study examined workplace aggression among a Dutch group of 174 prison workers at 10 penitentiaries in the Netherlands. The purpose of the study was to investigate the main and interaction effects of Type D personality and violence on posttraumatic stress disorder (PTSD). The results showed a significant interaction effect between the type of violence and Type D personality. Physically violated Type D individuals achieved the highest average score on the PTSD scale. Type D personality was found to have a strong main effect on PTSD.

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., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

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.

In this review we compare expression studies on monocyte subsets as an example to show the integrated possibilities of molecular databases and bioinformatic analysis tools. Monocytes have been recognized as cells with great plasticity and differentiation potential that play a pivotal role in revascularization processes, i.e. angiogenesis and arteriogenesis. To gain more insight in the relevant developmental programs, we compared the full-genome mRNA expression profiles of several distinct human monocyte subpopulations previously identified based on surface marker expression. These included classical and non-classical, M1 and M2 macrophages, circulating angiogenic cells (CAC), and non-monocyte-derived endothelial colony-forming cells (ECFC). Their transcriptional profiles revealed distinct and overlapping gene expression signatures and pathways reminiscent of utilization of transcription factors driving polarization into the different monocytic phenotypes. Hierarchical cluster analysis revealed that CAC are most related to M2 macrophages and unstimulated macrophages, and to a lesser extent to classical monocytes, and are quite distinct from M1 macrophages and ECFC. Analysis of the promoter region of CAC-expressed genes suggests that in particular the ETS family of transcription factors is important in CAC development. These analyses show the power of combining multiple datasets with existing databases on biological knowledge, to interpret full genome expression data., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To reduce long-term morbidity after revascularised acute myocardial infarction, different therapeutic strategies have been investigated. Cell therapy with mononuclear cells from bone marrow (BMMC) or peripheral blood (PBMC) has been proposed to attenuate the adverse processes of remodelling and subsequent heart failure. Previous trials have suggested that cell therapy may facilitate arrhythmogenesis. In the present substudy of the HEBE cell therapy trial, we investigated whether intracoronary cell therapy alters the prevalence of ventricular arrhythmias after 1 month or the rate of severe arrhythmogenic events (SAE) in the first year. In 164 patients of the trial we measured function and infarct size with cardiovascular magnetic resonance (CMR) imaging. Holter registration was performed after 1 month from which the number of triplets (3 successive PVCs) and ventricular tachycardias (VT, ≥4 successive PVCs) was assessed. Thirty-three patients (20%) showed triplets and/or VTs, with similar distribution amongst the groups (triplets: control n = 8 vs. BMMC n = 9, p = 1.00; vs. PBMC n = 10, p = 0.67. VT: control n = 9 vs. BMMC n = 9, p = 0.80; vs. PBMC n = 11, p = 0.69). SAE occurred in 2 patients in the PBMC group and 1 patient in the control group. In conclusion, intracoronary cell therapy is not associated with an increase in ventricular arrhythmias or SAE.

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., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In some myopathies, hypoxia can be the result of pathologic effects like muscle necrosis and abnormal blood flow. At the molecular level, the consequence of hypoxic conditions is not yet fully understood. Under stress conditions, many housekeeping gene mRNAs are translationally silenced, while translation of other mRNAs increases. Alterations to the pool of mRNAs available for translation lead to the formation of so-called stress granules containing both mRNAs and proteins. Stress granule formation and dynamics have been investigated using cells in culture, but have not yet been examined in vivo. In Drosophila embryonic muscles, we found that hypoxia induces the formation of sarcoplasmic granules containing the established stress granule markers RIN and dFMR1. Upon restoration of normoxia, the observed granules were decreased in size, indicating that their formation might be reversible. Employing photobleaching approaches, we found that a cytoplasmic reporter mRNA rapidly shuttles in and out of the granules. Hence, stress granules are highly dynamic complexes and not simple temporary storage sites. Although mRNA rapidly cycles through the granules, its movement throughout the muscle is, remarkably, spatially restricted by the presence of yet undefined myofiber domains. Our results suggest that in hypoxic muscles mRNA remains highly mobile; however, its movement throughout the muscle is restricted by certain boundaries. The development of this Drosophila hypoxia model makes it possible to study the formation and dynamics of stress granules and their associated mRNAs and proteins in a living organism.

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)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)