RESUMO
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 Vav1Cre/+Cpt1Afl/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 AdipoqCreERT2Atglfl/fl mice or local depletion of bone marrow adipocytes in AdipoqCreERT2iDTR 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.
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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.
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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.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células Mieloides/metabolismo , Idoso , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Cardiomiopatias/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Células Mieloides/patologia , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Miocardite/metabolismo , Miocardite/patologiaRESUMO
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.
Assuntos
Interferon Tipo I/metabolismo , Monócitos/transplante , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Remodelação Ventricular , Adulto , Idoso , Animais , Transplante de Medula Óssea/métodos , Feminino , Humanos , Interferon Tipo I/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Ventricular/efeitos dos fármacos , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologiaRESUMO
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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Macrófagos/fisiologia , Infarto do Miocárdio/imunologia , Animais , Polaridade Celular , Citocinas/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/imunologia , Miocárdio/patologia , Proteínas do Tecido Nervoso/metabolismo , Regeneração , Transdução de Sinais , Remodelação VentricularRESUMO
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.
Assuntos
Células-Tronco Hematopoéticas/fisiologia , Macrófagos/fisiologia , Monócitos/fisiologia , Células Mieloides/fisiologia , Infarto do Miocárdio/imunologia , Proteínas Nucleares/metabolismo , Receptores CCR2/metabolismo , Fatores de Transcrição/metabolismo , Animais , Movimento Celular/genética , Células Cultivadas , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Modelos Animais , Mielopoese/genética , Infarto do Miocárdio/cirurgia , Proteínas Nucleares/genética , RNA Interferente Pequeno/genética , Receptores CCR2/genética , Proteínas Repressoras , Fatores de Transcrição/genética , Cicatrização/genéticaRESUMO
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.
Assuntos
Circulação Colateral/fisiologia , Galectina 2/fisiologia , Inflamação/fisiopatologia , Macrófagos/fisiologia , Monócitos/fisiologia , Animais , Antígenos CD40/biossíntese , Diferenciação Celular , Células Cultivadas , Circulação Colateral/efeitos dos fármacos , Células Dendríticas/metabolismo , Galectina 2/deficiência , Galectina 2/genética , Galectina 2/farmacologia , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/biossíntese , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/fisiologia , Macrófagos/classificação , Macrófagos/efeitos dos fármacos , Receptor de Manose , Lectinas de Ligação a Manose/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Fenótipo , Ligação Proteica/efeitos dos fármacos , Células RAW 264.7 , Receptores de Superfície Celular/biossíntese , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Transdução de Sinais , Linfócitos T/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
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 3-5â days, and 4â months after AMI, all patients underwent cardiac MRI after 2â years. A follow-up for 5â 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 5â years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5±16.9â mL/m(2)) compared with (11.2±19.8â mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2±20.9â mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8±15.0â mL/m(2)) as compared with controls (3.0±16.3â mL/m(2), p=0.07), with again no difference between PBMC (3.3±18.8â 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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Transplante de Medula Óssea , Leucócitos Mononucleares/transplante , Infarto do Miocárdio/terapia , Feminino , Seguimentos , Ventrículos do Coração/patologia , Humanos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Intervenção Coronária Percutânea , Recidiva , Disfunção Ventricular Esquerda/epidemiologia , Disfunção Ventricular Esquerda/patologiaRESUMO
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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Macrófagos/fisiologia , Monócitos/fisiologia , Infarto do Miocárdio/imunologia , Isquemia Miocárdica/imunologia , Miocárdio/imunologia , Transferência Adotiva , Animais , Apoptose/efeitos dos fármacos , Transplante de Medula Óssea , Receptor 1 de Quimiocina CX3C , Divisão Celular , Toxina Diftérica/toxicidade , Feminino , Genes Reporter , Humanos , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Isquemia Miocárdica/patologia , Miocárdio/patologia , Parabiose , Fagocitose , Quimera por Radiação , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/fisiologiaRESUMO
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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Transplante de Medula Óssea , Terapia Baseada em Transplante de Células e Tecidos/métodos , Leucócitos Mononucleares/transplante , Imageamento por Ressonância Magnética/métodos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/terapia , Miocárdio/patologia , Adulto , Idoso , Técnicas de Imagem de Sincronização Cardíaca , Terapia Combinada , Meios de Contraste , Circulação Coronária , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imagem Cinética por Ressonância Magnética , Masculino , Meglumina , Pessoa de Meia-Idade , Neovascularização Fisiológica , Compostos Organometálicos , Intervenção Coronária Percutânea , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
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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Monócitos/fisiologia , Infarto do Miocárdio/patologia , Baço/fisiologia , Idoso , Antígenos CD/metabolismo , Células da Medula Óssea/fisiologia , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Masculino , Monócitos/classificação , Infarto do Miocárdio/imunologia , Miocárdio/patologia , Baço/imunologiaAssuntos
Imunidade Celular/fisiologia , Infarto do Miocárdio/imunologia , Remodelação Ventricular/imunologia , Células Sanguíneas/imunologia , Previsões , Humanos , Imunidade Inata/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Infarto do Miocárdio/terapia , Células-Tronco/imunologia , Cicatrização/imunologiaRESUMO
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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Aterosclerose/etiologia , Aterosclerose/patologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Animais , Apolipoproteínas E/genética , Células-Tronco Hematopoéticas/citologia , Inflamação/complicações , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/citologia , Baço/citologia , Células-Tronco/citologiaRESUMO
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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Macrófagos/fisiologia , Monócitos/fisiologia , Infarto do Miocárdio/diagnóstico por imagem , Miocardite/diagnóstico por imagem , Idoso , Animais , Estudos de Casos e Controles , Feminino , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/imunologia , Miocardite/enzimologia , Miocardite/imunologia , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
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).