RESUMEN
BACKGROUND: Monocyte toll-like receptor 4 (TLR4) has been implicated in the pathogenesis of atherosclerosis with increased levels in myocardial infarction. The aim of this study was to assess the numbers of TLR4(+) monocytes in each monocyte subset in MI, the expression of TLR4 and association with markers of monocyte activation, inflammation, myocardial damage and postmyocardial infarction (MI) cardiac contractility. METHODS: Surface expression of TLR4 and numbers of TLR4-expressing monocytes were quantified by flow cytometry of venous blood in 50 patients with ST-elevation MI (STEMI), 48 with non-STEMI (NSTEMI) and 40 with stable coronary artery disease (CAD). These parameters were measured on days 1, 3, 7 and 30 post-MI in STEMI patients. Three monocyte subsets were defined as CD14(++) CD16(-) CCR2(+) (Mon1), CD14(++) CD16(+) CCR2(+) (Mon2) and CD14(+) CD16(++) CCR2(-) (Mon3). Plasma inflammatory cytokines were assessed using cytometric bead arrays. RESULTS: There was a significant increase in counts of TLR4(+) Mon1 and Mon2 in STEMI patients and TLR4(+) Mon2 in NSTEMI patients compared with controls with CAD. Monocyte TLR4(+) expression was similar between the groups, and was not changed during follow-up in STEMI patients. Plasma interleukin-6 (IL6) levels correlated positively with TLR4(+) Mon2 count (r = 0.54, P < 0.001), but negatively with TLR4 expression on Mon2 (r = -0.33, P = 0.021). CONCLUSION: Following treatment of acute MI, TLR4 expression by individual monocyte subsets is unchanged. An increase in TLR4(+) Mon1 and Mon2 count in patients with STEMI and TLR(+) Mon2 count in those with NSTEMI is due to an increase in monocyte subset count and not to changes in TLR4 expression. Monocyte counts but not TLR4 expression correlate positively with plasma IL6 levels. We suggest that TLR4 expression may not be a reliable marker of monocyte activation in MI.
Asunto(s)
Biomarcadores/análisis , Infarto del Miocardio/sangre , Anciano , Biomarcadores/sangre , Recuento de Células , Femenino , Citometría de Flujo , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Contracción Miocárdica/fisiología , FN-kappa B/sangre , Agregación Plaquetaria/fisiología , Pronóstico , Receptor Toll-Like 4RESUMEN
We report a case of successful surgical treatment of Q fever endocarditis with mitral valve repair in a 66-year old retired British soldier. Valve replacement is invariably undertaken in Q fever endocarditis due to the degree of valvular damage and concerns about eradicating the organism, Coxiella burnetii. Our unique case allowed valve repair since pre-existing myxomatous degeneration and subsequent posterior mitral valve leaflet prolapse resulted in significant excess valve tissue, allowing quadrangular resection of the damaged and perforated P2 portion of this leaflet. Follow-up at four years (including three years of antibiotic treatment) has confirmed excellent valve repair, with no echocardiographic, clinical or microbiological evidence of recurrence. We are only the second group to describe valve repair in a patient with chronic Q fever endocarditis. Valve repair is preferable to valve replacement for Q fever endocarditis, if technically possible.
Asunto(s)
Endocarditis Bacteriana/cirugía , Válvula Mitral/cirugía , Fiebre Q/complicaciones , Anciano , Antibacterianos/uso terapéutico , Coxiella burnetii , Endocarditis Bacteriana/tratamiento farmacológico , Endocarditis Bacteriana/microbiología , Humanos , Masculino , Fiebre Q/microbiologíaRESUMEN
BACKGROUND: Endothelial progenitor cells (EPCs) are known to be altered in heart failure (HF), but monocyte-derived EPCs in HF have not been assessed. We aimed to characterize monocyte-derived EPCs in systolic HF. METHODS AND RESULTS: We recruited 128 subjects with systolic HF: 50 South Asian (SA), 50 white, and 28 African-Caribbean (AC), for interethnic comparisons. Additionally, SAs with HF were compared with 40 SAs with coronary artery disease (CAD) without HF (disease controls [DCs]) and 40 SA healthy controls (HCs). Counts of CD34(+) and kinase domain receptor (KDR)(+) monocytes attributed to specific monocyte subsets (CD14(++) /CD16(-) [Mon1], CD14(++)/CD16(+) [Mon2], and CD14(+)/CD16(++) [Mon3]) and monocyte expression of vascular endothelial growth factor (VEGF) receptor 1 were analyzed by flow cytometry. We also enumerated CD34(+)/KDR(+) EPCs derived from mononuclear cells ('classic' EPC definition). RESULTS: SAs with HF had significantly reduced counts of CD34(+) monocytes, attributed to the Mon1 and Mon2 subsets. KDR(+) Mon1 counts were 4.5-fold increased in DCs as compared with HCs, but significantly reduced in HF subjects vs. DCs. VEGF receptor type 1 expression on Mon1 and Mon2 cells was significantly reduced in HF patients as compared with DCs. Also, CD34(+)/KDR(+) EPC numbers were reduced in HF subjects. Whites had significantly fewer KDR(+) Mon3 cells than ACs, but significantly more CD34(+) Mon2 cells than SAs and ACs. VEGF receptor type 1 expression by Mon1 cells was predictive for left ventricular ejection fraction after adjustment for ethnicity (ß = - 0.25. P = 0.039). CD34(+) Mon2 counts correlated with measures of microvascular endothelial function, and were predictive of the future risk of hospital admission. CONCLUSIONS: Circulating counts of monocyte-derived EPCs are significantly altered in HF, with significant ethnic differences in the levels of monocyte-derived EPCs.
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Antígenos CD34/inmunología , Células Endoteliales/patología , Insuficiencia Cardíaca/patología , Monocitos/patología , Células Madre/patología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/inmunología , Anciano , Estudios de Casos y Controles , Células Endoteliales/inmunología , Femenino , Citometría de Flujo , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Células Madre/inmunología , UltrasonografíaRESUMEN
AIM: Monocytes contribute to both myocardial damage and repair by virtue of subset heterogeneity. The dynamics and functional characteristics of the three human monocyte subsets, including the unique CD14++CD16+ subset, and their contributions to monocyte platelet aggregates (MPAs) following ST-elevation myocardial infarction (STEMI) are unknown. We aimed to examine dynamic changes and relation to left ventricular ejection fraction (LVEF) of the three human monocyte subsets and their aggregates with platelets following STEMI. METHODS: Three monocyte subsets, CD14++CD16-CCR2+ ('classical', Mon1), CD14++CD16+CCR2+ ('intermediate', Mon2) and CD14+CD16++CCR2- ('non-classical', Mon3), and their contribution to MPAs were analyzed by flow cytometry in 50 patients with STEMI, 40 patients with stable coronary artery disease (CAD) and 40 healthy volunteers. Study parameters were measured within 24 h of primary percutaneous coronary intervention (PCI) (day1) and on days 3, 7 and 30. Monocyte activation was assessed by measuring the nuclear factor κB (NFκB) pathway. LVEF was assessed 6 weeks after STEMI. Correlations between monocyte subsets/MPAs and plasma cytokines and troponin were assessed. RESULTS: We observed marked differences in subset dynamics, with a prominent increase in Mon2 (P < 0.0001) but no changes in Mon3. Significant increases in Mon2 CD14 (P = 0.002) and CCR2 (P < 0.0001) expression, and reduction in CD16 expression (P = 0.001) were seen. NFκB pathway activity increased most prominently in Mon2 (P = 0.007). Mon2 count correlated with peak troponin (r = 0.31, P = 0.04) and plasma interleukin (IL)-6 (r = 0.65, P < 0.0001) and IL-10 (r = 0.34, P = 0.017). Mon1 correlated with IL-6 (r = 0.55, P < 0.0001). Reduced Mon2 expression of CD16 on day 1 was independently predictive of higher LVEF (ß = -0.37, P = 0.013). The increase in MPA count following STEMI persisted at 1 month. CONCLUSION: The Mon2 'intermediate' subset has unique dynamic and functional characteristics following STEMI and significant correlations with troponin, plasma cytokines and convalescent left ventricular function. The persistent increase in MPA count 30 days after STEMI may affect monocyte subset functional activity.
Asunto(s)
Plaquetas/patología , Receptores de Lipopolisacáridos/inmunología , Monocitos/inmunología , Infarto del Miocardio/inmunología , Receptores de IgG/inmunología , Anciano , Agregación Celular , Quimiocina CCL2/sangre , Citocinas/sangre , Electrocardiografía , Femenino , Citometría de Flujo , Proteínas Ligadas a GPI/inmunología , Humanos , Masculino , Persona de Mediana Edad , Monocitos/patología , Infarto del Miocardio/fisiopatologíaRESUMEN
The complexity of interactions underlying the elaboration of myelin has been extensively demonstrated. We provide evidence that signals promoting myelination are not confined to the normal developmental time window for myelination and persist well into adult life. The 2-50 mutant, described previously, carries a c-myc transgene regulated by a myelin basic protein promoter. This mutant is characterised by severe hypomyelination and abnormal oligodendrocytes in early life, followed by loss of the phenotype and normal longevity. We show that c-myc expression in early oligodendrocyte development results in a substantial reduction of cells of this lineage. However, apparent complete recovery, associated with loss of c-myc expression, axonal survival, and gradual myelin accumulation, is observed by 4 months of age. Thus, stimulation of myelination continues during adult life until normal myelin levels are established. We propose that this mutant may contribute to the characterisation of oligodendrocyte responses to myelinating signals.