Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson's disease.

Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson's disease (PD) risk across seven diverse ancestry populations. Methods: We conducted a multi-stage study, testing PRS models in predicting PD status across seven different ancestries applying three approaches: 1) PRS adjusted by gender and age; 2) PRS adjusted by gender, age and principal components (PCs); and 3) PRS adjusted by gender, age and percentage of population admixture. These models were built using the largest four population-specific summary statistics of PD risk to date (base data) and individual level data obtained from the Global Parkinson's Genetics Program (target data). We performed power calculations to estimate the minimum sample size required to conduct these analyses. A total of 91 PRS models were developed to investigate cumulative known genetic variation associated with PD risk and age of onset in a global context. Results: We observed marked heterogeneity in risk estimates across non-European ancestries, including East Asians, Central Asians, Latino/Admixed Americans, Africans, African admixed, and Ashkenazi Jewish populations. Risk allele patterns for the 90 risk variants yielded significant differences in directionality, frequency, and magnitude of effect. PRS did not improve in performance when predicting disease status using similar base and target data across multiple ancestries, demonstrating that cumulative PRS models based on current known risk are inherently biased towards European populations. We found that PRS models adjusted by percentage of admixture outperformed models that adjusted for conventional PCs in highly admixed populations. Overall, the clinical utility of our models in individually predicting PD status is limited in concordance with the estimates observed in European populations. Interpretation: This study represents the first comprehensive assessment of how PRS models predict PD risk and age at onset in a multi-ancestry fashion. Given the heterogeneity and distinct genetic architecture of PD across different populations, our assessment emphasizes the need for larger and diverse study cohorts of individual-level target data and well-powered ancestry-specific summary statistics. Our current understanding of PD status unraveled through GWAS in European populations is not generally applicable to other ancestries. Future studies should integrate clinical and *omics level data to enhance the accuracy and predictive power of PRS across diverse populations.

Exploring the genetic and genomic connection underlying neurodegeneration with brain iron accumulation and the risk for Parkinson's disease.

Neurodegeneration with brain iron accumulation (NBIA) represents a group of neurodegenerative disorders characterized by abnormal iron accumulation in the brain. In Parkinson's Disease (PD), iron accumulation is a cardinal feature of degenerating regions in the brain and seems to be a key player in mechanisms that precipitate cell death. The aim of this study was to explore the genetic and genomic connection between NBIA and PD. We screened for known and rare pathogenic mutations in autosomal dominant and recessive genes linked to NBIA in a total of 4481 PD cases and 10,253 controls from the Accelerating Medicines Partnership Parkinsons' Disease Program and the UKBiobank. We examined whether a genetic burden of NBIA variants contributes to PD risk through single-gene, gene-set, and single-variant association analyses. In addition, we assessed publicly available expression quantitative trait loci (eQTL) data through Summary-based Mendelian Randomization and conducted transcriptomic analyses in blood of 1886 PD cases and 1285 controls. Out of 29 previously reported NBIA screened coding variants, four were associated with PD risk at a nominal p value < 0.05. No enrichment of heterozygous variants in NBIA-related genes risk was identified in PD cases versus controls. Burden analyses did not reveal a cumulative effect of rare NBIA genetic variation on PD risk. Transcriptomic analyses suggested that DCAF17 is differentially expressed in blood from PD cases and controls. Due to low mutation occurrence in the datasets and lack of replication, our analyses suggest that NBIA and PD may be separate molecular entities.

Overexpression of alpha-synuclein promotes both cell proliferation and cell toxicity in human SH-SY5Y neuroblastoma cells.

Alpha-Synuclein (aSyn) is a chameleon-like protein. Its overexpression and intracellular deposition defines neurodegenerative α-synucleinopathies including Parkinson's disease. Whether aSyn up-regulation is the cause or the protective reaction to α-synucleinopathies remains unresolved. Remarkably, the accumulation of aSyn is involved in cancer. Here, the neuroblastoma SH-SY5Y cell line was genetically engineered to overexpress aSyn at low and at high levels. aSyn cytotoxicity was assessed by the MTT and vital-dye exclusion methods, observed at the beginning of the sub-culture of low-aSyn overexpressing neurons when cells can barely proliferate exponentially. Conversely, high-aSyn overexpressing cultures grew at high rates while showing enhanced colony formation compared to low-aSyn neurons. Cytotoxicity of aSyn overexpression was indirectly revealed by the addition of pro-oxidant rotenone. Pretreatment with partially reduced graphene oxide, an apoptotic agent, increased toxicity of rotenone in low-aSyn neurons, but, it did not in high-aSyn neurons. Consistent with their enhanced proliferation, high-aSyn neurons showed elevated levels of SMP30, a senescence-marker protein, and the mitosis Ki-67 marker. High-aSyn overexpression conferred to the carcinogenic neurons heightened tumorigenicity and resistance to senescence compared to low-aSyn cells, thus pointing to an inadequate level of aSyn stimulation, rather than the aSyn overload itself, as one of the factors contributing to α-synucleinopathy.

Graphene Oxide and Reduced Derivatives, as Powder or Film Scaffolds, Differentially Promote Dopaminergic Neuron Differentiation and Survival.

Emerging scaffold structures made of carbon nanomaterials, such as graphene oxide (GO) have shown efficient bioconjugation with common biomolecules. Previous studies described that GO promotes the differentiation of neural stem cells and may be useful for neural regeneration. In this study, we examined the capacity of GO, full reduced (FRGO), and partially reduced (PRGO) powder and film to support survival, proliferation, differentiation, maturation, and bioenergetic function of a dopaminergic (DA) cell line derived from the mouse substantia nigra (SN4741). Our results show that the morphology of the film and the species of graphene (GO, PRGO, or FRGO) influences the behavior and function of these neurons. In general, we found better biocompatibility of the film species than that of the powder. Analysis of cell viability and cytotoxicity showed good cell survival, a lack of cell death in all GO forms and its derivatives, a decreased proliferation, and increased differentiation over time. Neuronal maturation of SN4741 in all GO forms, and its derivatives were assessed by increased protein levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), the glutamate inward rectifying potassium channel 2 (GIRK2), and of synaptic proteins, such as synaptobrevin and synaptophysin. Notably, PRGO-film increased the levels of Tuj1 and the expression of transcription factors specific for midbrain DA neurons, such as Pitx3, Lmx1a, and Lmx1b. Bioenergetics and mitochondrial dysfunction were evaluated by measuring oxygen consumption modified by distinct GO species and were different between powder and film for the same GO species. Our results indicate that PRGO-film was the best GO species at maintaining mitochondrial function compared to control. Finally, different GO forms, and particularly PRGO-film was also found to prevent the loss of DA cells and the decrease of the α-synuclein (α-syn) in a molecular environment where oxidative stress has been induced to model Parkinson's disease. In conclusion, PRGO-film is the most efficient graphene species at promoting DA differentiation and preventing DA cell loss, thus becoming a suitable scaffold to test new drugs or develop constructs for Parkinson's disease cell replacement therapy.

Exploring the Interaction Between eIF2α Dysregulation, Acute Endoplasmic Reticulum Stress and DYT1 Dystonia in the Mammalian Brain.

DYT1 dystonia is a neurological disease caused by dominant mutations in the TOR1A gene, encoding for the endoplasmic reticulum (ER)-resident protein torsinA. Recent reports linked expression of the DYT1-causing protein with dysregulation of eIF2α, a key component of the cellular response to ER stress known as the unfolded protein response (UPR). However, the response of the DYT1 mammalian brain to acute ER stress inducers has not been evaluated in vivo. We hypothesized that torsinA regulates the neuronal UPR and expression of its mutant form would alter this process. TorsinA was post-transcriptionally upregulated upon acute ER stress in different models, suggesting a role in this response. Moreover, increased basal phosphorylation of eIF2α in DYT1 transgenic rats was associated with an abnormal response to acute ER stress. Finally, an unbiased RNA-Seq-based transcriptomic analysis of embryonic brain tissue in heterozygous and homozygous DYT1 knockin mice confirmed the presence of eIF2α dysregulation in the DYT1 brain. In sum, these findings support previous reports linking torsinA function, eIF2α signaling and the neuronal response to ER stress in vivo. Furthermore, we describe novel protocols to investigate neuronal ER stress in cultured neurons and in vivo.

Cell survival and differentiation with nanocrystalline glass-like carbon using substantia nigra dopaminergic cells derived from transgenic mouse embryos.

Regenerative medicine requires, in many cases, physical supports to facilitate appropriate cellular architecture, cell polarization and the improvement of the correct differentiation processes of embryonic stem cells, induced pluripotent cells or adult cells. Because the interest in carbon nanomaterials has grown within the last decade in light of a wide variety of applications, the aim of this study was to test and evaluate the suitability and cytocompatibility of a particular nanometer-thin nanocrystalline glass-like carbon film (NGLC) composed of curved graphene flakes joined by an amorphous carbon matrix. This material is a disordered structure with high transparency and electrical conductivity. For this purpose, we used a cell line (SN4741) from substantia nigra dopaminergic cells derived from transgenic mouse embryos. Cells were cultured either in a powder of increasing concentrations of NGLC microflakes (82±37µm) in the medium or on top of nanometer-thin films bathed in the same culture medium. The metabolism activity of SN4741 cells in presence of NGLC was assessed using methylthiazolyldiphenyl-tetrazolium (MTT) and apoptosis/necrosis flow cytometry assay respectively. Growth and proliferation as well as senescence were demonstrated by western blot (WB) of proliferating cell nuclear antigen (PCNA), monoclonal phosphorylate Histone 3 (serine 10) (PH3) and SMP30 marker. Specific dopaminergic differentiation was confirmed by the WB analysis of tyrosine hydroxylase (TH). Cell maturation and neural capability were characterized using specific markers (SYP: synaptophysin and GIRK2: G-protein-regulated inward-rectifier potassium channel 2 protein) via immunofluorescence and coexistence measurements. The results demonstrated cell positive biocompatibility with different concentrations of NGLC. The cells underwent a process of adaptation of SN4741 cells to NGLC where their metabolism decreases. This process is related to a decrease of PH3 expression and significant increase SMP30 related to senescence processes. After 7 days, the cells increased the expression of TH and PCNA that is related to processes of DNA replication. On the other hand, cells cultured on top of the film showed axonal-like alignment, edge orientation, and network-like images after 7 days. Neuronal capability was demonstrated to a certain extent through the analysis of significant coexistence between SYP and GIRK2. Furthermore, we found a direct relationship between the thickness of the films and cell maturation. Although these findings share certain similarities to our previous findings with graphene oxide and its derivatives, this particular nanomaterial possesses the advantages of high conductivity and transparency. In conclusion, NGLC could represent a new platform for biomedical applications, such as for use in neural tissue engineering and biocompatible devices.

Serum levels of interleukin-2 predict the recurrence of atrial fibrillation after pulmonary vein ablation.

AIMS: Interleukin-2 has a significant antitumor activity in some types of cancer, and has been associated with the development of atrial fibrillation (AF). In addition, IL-2 serum levels in recent onset AF have been related with pharmaceutical cardioversion outcomes. We evaluated the hypothesis that a relationship exists between inflammation and the outcome of catheter ablation of AF. METHODS: We studied 44 patients with paroxysmal AF who underwent catheter ablation. Patients with structural heart disease, coronary artery or valve disease, active inflammatory disease, known or suspected neoplasm, endocrinopathies, or exposure to anti-inflammatory drugs were excluded. All study participants underwent evaluation with a standardized protocol, including echocardiography, and cytokine levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, tumour necrosis factor-alpha, and gamma-interferon determination before procedure. Clinical and electrocardiographic follow-up were performed with Holter-ECG at 3, 6 and 12months in order to know if sinus rhythm was maintained. RESULTS: After catheter ablation of the 44 patients included (53±10years, 27.3% female), all patients returned to sinus rhythm. During the first year of follow-up seven patients (15.9%) experienced recurrence of AF. The demographics, clinical and echocardiographic features, and pharmacological treatments of these patients were similar to those who maintained sinus rhythm. The only independent factor predictive of recurrence of AF was an elevated level of IL-2 (OR 1.18, 95% CI 1.12-1.38). CONCLUSIONS: High serum levels of interleukin-2, a pro-inflammatory non-vascular cytokine, are associated with the recurrence of AF in patients undergoing catheter ablation.

Identification of reference genes for quantitative RT-PCR in ascending aortic aneurysms.

Hypertension and congenital aortic valve malformations are frequent causes of ascending aortic aneurysms. The molecular mechanisms of aneurysm formation under these circumstances are not well understood. Reference genes for gene activity studies in aortic tissue that are not influenced by aortic valve morphology and its hemodynamic consequences, aortic dilatation, hypertension, or antihypertensive medication are not available so far. This study determines genes in ascending aortic tissue that are independent of these parameters. Tissue specimens from dilated and undilated ascending aortas were obtained from 60 patients (age ≤70 years) with different morphologies of the aortic valve (tricuspid undilated n = 24, dilated n = 11; bicuspid undilated n = 6, dilated n = 15; unicuspid dilated n = 4). Of the studied individuals, 36 had hypertension, and 31 received ACE inhibitors or AT1 receptor antagonists. The specimens were obtained intraoperatively from the wall of the ascending aorta. We analyzed the expression levels of 32 candidate reference genes by quantitative RT-PCR (RT-qPCR). Differential expression levels were assessed by parametric statistics. The expression analysis of these 32 genes by RT-qPCR showed that EIF2B1, ELF1, and PPIA remained constant in their expression levels in the different specimen groups, thus being insensitive to aortic valve morphology, aortic dilatation, hypertension, and medication with ACE inhibitors or AT1 receptor antagonists. Unlike many other commonly used reference genes, the genes EIF2B1, ELF1, and PPIA are neither confounded by aortic comorbidities nor by antihypertensive medication and therefore are most suitable for gene expression analysis of ascending aortic tissue.

Characterization of adult stem/progenitor cell populations from bone marrow in a three-dimensional collagen gel culture system.

Stem cell transplantation therapy using mesenchymal stem cells (MSCs) is considered a useful strategy. Although MSCs are commonly isolated by exploiting their plastic adherence, several studies have suggested that there are other populations of stem and/or osteoprogenitor cells that are removed from primary culture during media replacement. Therefore, we developed a three-dimensional (3D) culture system in which adherent and nonadherent stem cells are selected and expanded. Here, we described the characterization of 3D culture-derived cell populations in vitro and the capacity of these cells to differentiate into bone and/or cartilage tissue when placed inside of demineralized bone matrix (DBM) cylinders, implanted subcutaneously into the backs of rat for 2, 4, and 8 weeks. Our results demonstrates that 3D culture cells were a heterogeneous population of uncommitted cells that express pluripotent-, hematopoietic-, mesenchymal-, and endothelial-specific markers in vitro and can undergo osteogenic differentiation in vivo.

Factores que influyen en la liberación de células endoteliales progenitoras y citocinas angiogénicas tras un infarto de miocardio extenso / Factors influencing mobilisation of endothelial progenitor cells and angiogenic cytokines after an extensive acute myocardial infarction

Fundamento y objetivo: Tras un infarto de miocardio (IM), las células progenitoras endoteliales (CPE) procedentes de la médula ósea son movilizadas hacia sangre periférica. El objetivo de nuestro trabajo fue estudiar los factores que influyen en dicha movilización celular espontánea. Pacientes y metodo: En este estudio se han analizado en 47 pacientes con IM extenso (definido por una fracción de eyección ventricular izquierda [FEVI] <50% por ecocardiografía en la primera semana post-IM), las poblaciones de CPE en sangre periférica (porcentaje sobre células mononucleares periféricas) que expresaban CD133+, CD34+, KDR+, CXCR4+, así como las citoquinas vascular endothelial growth factor (VEGF, «factor de crecimiento vascular endotelial»), stromal cell-derived factor 1 (SDF-1, «factor derivado del estroma tipo 1» y trombospondina 1, determinadas en el día 5±2,5 tras el IM. Resultados: La extensión del IM se correlacionó con el número de células movilizadas (r=040; p=0,011 entre pico de CPK y CD133+). Los pacientes que no recibieron reperfusión en fase aguda (fibrinólisis/angioplastia) (34%) presentaron más células CD34+CXCR4+ (mediana [rango intercuartílico]: 2.401 [498-7.004] frente a 999 [100-1.600]; p=0,048), así como una fuerte correlación entre VEGF y CD133+CD34+KDR+ (r=0,84; p<0,01), entre SDF-1 y CD34+CXCR4+ (r=0,67; p<0,01), y entre ambas citoquinas (r=0,57; p=0,01). En los pacientes reperfundidos, la correlación VEGF y CD133+CD34+KDR+ fue menor (r=0,38; p=0,03) y desapareció la correlación de SDF-1 con CD34+CXCR4+ y con VEGF. Tras el análisis multivariante, la presencia de VEGF>7pg/ml (p<0,01) fue predictora de la movilización de CD133+CD34+KDR+, mientras que la hipertensión (p=0,055) mostró una tendencia. La diabetes (p=0,045) lo fue sobre el número de CD34+CXCR4+, presentando el tratamiento de reperfusión (p=0,054) una tendencia sobre esta subpoblación (AU)

Background and objectives: Following an acute myocardial infarction (AMI), bone-marrow derived endothelial progenitor cells (EPC) are mobilised into the peripheral blood. Our aim was to examine the factors influencing this spontaneous cell mobilisation.Patients and methods: In this study we analysed 47 patients with extensive AMI (left ventricular ejection fraction [LVEF] <50% by echocardiography during the first week post-AMI); we studied the peripheral blood EPC populations expressing CD133+, CD34+, KDR+, CXCR4+, as well as the cytokines VEGF (vascular endothelial growth factor), SDF-1 (stromal cell-derived factor 1) and TSP-1 (thrombospondin 1), measured on day 5±2.5 after AMI. Results: The extension of AMI (CPK peak) correlated with the number of CD133+ mobilised cells: (r=0.40; P=.011). Patients who did not receive perfusion during the acute phase (34%) had more CD34+CXCR4+ cells with a median (interquartile ranges) of 2,401 (498-7,004) vs. 999 (100-1,600), P=.048, and strong correlations between VEGF and CD133+CD34+KDR+ (r=.84; P<.01) and SDF-1 and CD34+CXCR4+ (r=.67; P<.01), and between these 2 cytokines (r=.57; P=.01). In the reperfused patients, the correlation between VEGF and CD133+CD34+KDR+ was lower (r=.38; P=.03) and the correlation between SDF-1 and CD34+CXCR4+ and VEGF disappeared. Multivariate analysis showed that a VEGF >7pg/mL (P<.01) predicted the mobilisation of CD133+CD34+KDR+, whereas hypertension showed a trend (P=.055). Diabetes (P=.045) predicted the number of CD34+CXCR4+, with reperfusion treatment showing a trend in this subpopulation (P=.054). Conclusions:Mobilisation of progenitor cells after AMI is influenced by factors such as diabetes and the cytokine VEGF. Hypertension and reperfusion therapy during the acute phase also tend to influence the cell response (AU)

[Factors influencing mobilisation of endothelial progenitor cells and angiogenic cytokines after an extensive acute myocardial infarction]. / Factores que influyen en la liberación de células endoteliales progenitoras y citocinas angiogénicas tras un infarto de miocardio extenso.

BACKGROUND AND OBJECTIVES: Following an acute myocardial infarction (AMI), bone-marrow derived endothelial progenitor cells (EPC) are mobilised into the peripheral blood. Our aim was to examine the factors influencing this spontaneous cell mobilisation. PATIENTS AND METHODS: In this study we analysed 47 patients with extensive AMI (left ventricular ejection fraction [LVEF] <50% by echocardiography during the first week post-AMI); we studied the peripheral blood EPC populations expressing CD133(+), CD34(+), KDR(+), CXCR4(+), as well as the cytokines VEGF (vascular endothelial growth factor), SDF-1 (stromal cell-derived factor 1) and TSP-1 (thrombospondin 1), measured on day 5±2.5 after AMI. RESULTS: The extension of AMI (CPK peak) correlated with the number of CD133(+) mobilised cells: (r=0.40; P=.011). Patients who did not receive perfusion during the acute phase (34%) had more CD34(+)CXCR4(+) cells with a median (interquartile ranges) of 2,401 (498-7,004) vs. 999 (100-1,600), P=.048, and strong correlations between VEGF and CD133(+)CD34(+)KDR(+) (r=.84; P<.01) and SDF-1 and CD34(+)CXCR4(+) (r=.67; P<.01), and between these 2 cytokines (r=.57; P=.01). In the reperfused patients, the correlation between VEGF and CD133(+)CD34(+)KDR(+) was lower (r=.38; P=.03) and the correlation between SDF-1 and CD34(+)CXCR4(+) and VEGF disappeared. Multivariate analysis showed that a VEGF >7pg/mL (P<.01) predicted the mobilisation of CD133(+)CD34(+)KDR(+), whereas hypertension showed a trend (P=.055). Diabetes (P=.045) predicted the number of CD34(+)CXCR4(+), with reperfusion treatment showing a trend in this subpopulation (P=.054). CONCLUSIONS: Mobilisation of progenitor cells after AMI is influenced by factors such as diabetes and the cytokine VEGF. Hypertension and reperfusion therapy during the acute phase also tend to influence the cell response.

La extensión de la enfermedad coronaria determina la movilización de las células progenitoras endoteliales y las citocinas tras un primer infarto de miocardio con elevación del ST / Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation

Introducción y objetivos. La enfermedad coronaria multivaso es un importante factor pronóstico postinfarto a pesar de nuevas formas de reperfusión como la angioplastia primaria. El objetivo del presente estudio es determinar la secuencia de variación de diferentes poblaciones de células progenitoras endoteliales y factores angiogénicos (factor de crecimiento endotelial vascular, factor de crecimiento hepatocitario) según el grado de extensión de la enfermedad coronaria. Métodos. Estudiamos la cinética de liberación en 32 pacientes ingresados por un primer infarto, agrupados según tuvieran enfermedad coronaria monovaso o multivaso y 26 sujetos que constituyen el grupo control. Resultados. Los pacientes presentaban un mayor número de células progenitoras endoteliales y citocinas angiogénicas que los controles en las tres determinaciones realizadas (al ingreso, día 3 y día 7) de las siguientes subpoblaciones: CD34, CD34+CD133+, CD34+KDR+ y CD34+CD133+KDR+CD45+ (débil); este último era mayor el día 7. Los valores de las tres poblaciones analizadas eran mayores en los pacientes con enfermedad coronaria monovaso en las tres determinaciones. Las cifras del factor de crecimiento endotelial vascular subían durante la primera semana y las del factor de crecimiento hepatocitario mostraron un pico precoz al ingreso. No apreciamos diferencias significativas en las variaciones de citocinas según el grado de extensión de la enfermedad coronaria. Conclusiones. Aunque las cinéticas de liberación de diferentes poblaciones de células progenitoras endoteliales en pacientes con un primer infarto agudo de miocardio con enfermedad monovaso con enfermedad multivaso fueron similares, su número fue mayor en los pacientes con enfermedad coronaria monovaso. Las cifras del factor de crecimiento endotelial vascular ascendieron durante la primera semana y las del factor de crecimiento hepatocitario muestran un pico precoz al ingreso (AU)

Introduction and objectives. Multivessel coronary disease is still a postinfarction prognostic marker despite new forms of reperfusion, such as primary angioplasty. The aim of this study was to determine the time sequence of various sets of endothelial progenitor cells and angiogenic cytokines (vascular endothelial growth factor, hepatocyte growth factor) according to the degree of extension of the postinfarction coronary disease. Methods. We studied the release kinetics in 32 patients admitted for a first myocardial infarction with ST elevation, grouped according to whether they had single or multivessel disease, and 26 controls. Results. The patients had a higher number of endothelial progenitor cells and angiogenic cytokines than the controls at all 3 measurements (admission, day 3, and day 7) of the following subsets: CD34, CD34+CD133+, CD34+KDR+, and CD34+CD133+KDR+CD45+(weak); this latter was higher on day 7. The levels of these cell subsets were all higher in the patients with single-vessel disease and at all 3 measurements. The vascular endothelial growth factor levels were raised during the first week and the hepatocyte growth factor showed an early peak on admission for infarction. No significant differences were seen in the cytokines according to coronary disease extension. Conclusions. Although the release kinetics of different subsets of endothelial progenitor cells in patients with a first acute myocardial infarction with ST elevation was similar in those with single vessel disease to those with multivessel disease, the number of circulating endothelial progenitor cells was greater in the patients with single vessel disease. The vascular endothelial growth factor levels were raised during the first postinfarction week and the hepatocyte growth factor were higher on admission (AU)

[Coronary disease extension determines mobilization of endothelial progenitor cells and cytokines after a first myocardial infarction with ST elevation]. / La extensión de la enfermedad coronaria determina la movilización de las células progenitoras endoteliales y las citocinas tras un primer infarto de miocardio con elevación del ST.

INTRODUCTION AND OBJECTIVES: Multivessel coronary disease is still a postinfarction prognostic marker despite new forms of reperfusion, such as primary angioplasty. The aim of this study was to determine the time sequence of various sets of endothelial progenitor cells and angiogenic cytokines (vascular endothelial growth factor, hepatocyte growth factor) according to the degree of extension of the postinfarction coronary disease. METHODS: We studied the release kinetics in 32 patients admitted for a first myocardial infarction with ST elevation, grouped according to whether they had single or multivessel disease, and 26 controls. RESULTS: The patients had a higher number of endothelial progenitor cells and angiogenic cytokines than the controls at all 3 measurements (admission, day 3, and day 7) of the following subsets: CD34, CD34+CD133+, CD34+KDR+, and CD34+CD133+KDR+CD45+(weak); this latter was higher on day 7. The levels of these cell subsets were all higher in the patients with single-vessel disease and at all 3 measurements. The vascular endothelial growth factor levels were raised during the first week and the hepatocyte growth factor showed an early peak on admission for infarction. No significant differences were seen in the cytokines according to coronary disease extension. CONCLUSIONS: Although the release kinetics of different subsets of endothelial progenitor cells in patients with a first acute myocardial infarction with ST elevation was similar in those with single vessel disease to those with multivessel disease, the number of circulating endothelial progenitor cells was greater in the patients with single vessel disease. The vascular endothelial growth factor levels were raised during the first postinfarction week and the hepatocyte growth factor were higher on admission.

Influence of preinfarction angina on the release kinetics of endothelial progenitor cells and cytokines during the week after infarction.

BACKGROUND: Preinfarction angina, a possible form of ischaemic preconditioning, improves the prognosis in patients who experience a major ischaemic event; though the associated pathophysiology is not yet fully understood. The aim of this study was to determine the possible involvement of endothelial progenitor cells (EPC), the vascular endothelial growth factor (VEGF) and the hepatocyte growth factor (HGF) in the development of preinfarction angina. METHODS AND RESULTS: We studied 41 patients (60·5 ± 12 years; 34% women) and 14 healthy controls; 43·9% of the patients had preinfarction angina. No differences were found in the baseline characteristics of the two groups. Although the EPC, VEGF and HGF were raised as compared with the control group, no significant differences were found according to the presence or absence of preinfarction angina in the levels of EPC (baseline, P = 0·25; day 3, P = 0·11; day 7, P = 0·32), VEGF (baseline, P = 0·96; day 3, P = 0·06; day 7, P = 0·57) or HGF (baseline, P = 0·18; day 3, P = 1; day 7, P = 0·86). An association was seen in the patients who had preinfarction angina between the EPC levels at baseline and on days 3 and 7 and the HGF on admission with the time from the angina to the STEMI (ß = -0·070; ß = -0·066; ß = -0·081; ß = -80·16; P < 0·05), showing a reduction in the level of EPC cells for each hour passed since the event. CONCLUSIONS: No differences were found in the release kinetics of EPC, VEGF or HGF after a first infarction according to whether the patients had angina during the week before the infarction.

Insulin receptor substrate-1 expression is increased in circulating leukocytes of patients with acute coronary syndrome.

The mechanisms underlying the increased risk of cardiovascular disease associated with diabetes mellitus (DM) are not fully defined. Insulin resistance in human metabolic syndrome patients is associated with decreased expression of the insulin receptor substrate-2- (Irs2-) AKT2 axis in mononuclear leukocytes (MLs). Moreover, acute coronary syndrome (ACS) has been linked through genome-wide association studies to the 2q36-q37.3 locus, which contains the Irs1 gene. Here, we investigated the expression of insulin-signaling pathway genes in MLs from patients with DM, ACS, and ACS plus DM. Quantitative real-time PCR expression studies showed no differences in the mRNA levels of Irs2, Akt2, and Akt1 among all patients. However, Irs1 mRNA expression was significantly increased in patients with ACS-diabetics and nondiabetics-compared with diabetic patients without ACS (P < .02 and P < .005, resp.). The present study reveals for the first time an association between increased Irs1 mRNA levels in MLs of patients with ACS which is not related to DM.

Resident and non-resident stem cells in acute myocardial infarction.

Cardiovascular disease is the leading cause of death in developed countries. Acute myocardial infarction (AMI) is the result of hypoxia leading to cardiomyocyte death. This causes loss of function of contractile tissue, which is replaced by non-contractile fibrous tissue affecting left ventricular ejection fraction (LVEF). One of the current approaches to recover LVEF after an AMI is focused on the search for functional cells to replace the dead tissue, via implantation in the heart of autologous progenitor cells with a regenerative capacity. This review classifies these cells into two types: a) non-resident cells and b) resident cells within the cardiac tissue. We provide an overall view of the various subpopulations and their markers, based, in animal and human models from the early pioneering work to the latest findings.

Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs.

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.