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Many diseases linked with ethnic health disparities associate with changes in microbial communities in the United States, but the causes and persistence of ethnicity-associated microbiome variation are not understood. For instance, microbiome studies that strictly control for diet across ethnically diverse populations are lacking. Here, we performed multiomic profiling over a 9-day period that included a 4-day controlled vegetarian diet intervention in a defined geographic location across 36 healthy Black and White females of similar age, weight, habitual diets, and health status. We demonstrate that individuality and ethnicity account for roughly 70% to 88% and 2% to 10% of taxonomic variation, respectively, eclipsing the effects a short-term diet intervention in shaping gut and oral microbiomes and gut viromes. Persistent variation between ethnicities occurs for microbial and viral taxa and various metagenomic functions, including several gut KEGG orthologs, oral carbohydrate active enzyme categories, cluster of orthologous groups of proteins, and antibiotic-resistant gene categories. In contrast to the gut and oral microbiome data, the urine and plasma metabolites tend to decouple from ethnicity and more strongly associate with diet. These longitudinal, multiomic profiles paired with a dietary intervention illuminate previously unrecognized associations of ethnicity with metagenomic and viromic features across body sites and cohorts within a single geographic location, highlighting the importance of accounting for human microbiome variation in research, health determinants, and eventual therapies. Trial Registration: ClinicalTrials.gov ClinicalTrials.gov Identifier: NCT03314194.
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Microbioma Gastrointestinal , Microbiota , Bactérias/genética , Etnicidade , Fezes , Feminino , Microbioma Gastrointestinal/genética , Humanos , Microbiota/genética , ViromaRESUMO
BACKGROUND AND AIMS: The cardiometabolic disease-associated metabolite, alpha-aminoadipic acid (2-AAA) is formed from the breakdown of the essential dietary amino acid lysine. However, it was not known whether elevated plasma levels of 2-AAA are related to dietary nutrient intake. We aimed to determine whether diet is a determinant of circulating 2-AAA in healthy individuals, and whether 2-AAA is altered in response to dietary modification. METHODS AND RESULTS: We investigated the association between 2-AAA and dietary nutrient intake in a cross-sectional study of healthy individuals (N = 254). We then performed a randomized cross-over dietary intervention trial to investigate the effect of lysine supplementation (1 week) on 2-AAA in healthy individuals (N = 40). We further assessed the effect of a vegetarian diet on 2-AAA in a short-term (4-day) dietary intervention trial in healthy omnivorous women (N = 35). We found that self-reported dietary intake of animal products, including meat, poultry, and seafood, was associated with higher plasma 2-AAA cross-sectionally (P < 0.0001). Supplementary dietary lysine (5g/day) caused no significant increase in plasma 2-AAA; however, plasma 2-AAA was altered by general dietary modification. Further, plasma 2-AAA was significantly reduced by a short-term vegetarian diet (P = 0.003). CONCLUSION: We identified associations between plasma 2-AAA and consumption of animal products, which were validated in a vegetarian dietary intervention trial, but not in a trial designed to specifically increase the 2-AAA amino acid precursor lysine. Further studies are warranted to investigate whether implementation of a vegetarian diet improves cardiometabolic risk in individuals with elevated 2-AAA.
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Ácido 2-Aminoadípico , Biomarcadores , Estudos Cross-Over , Dieta Vegetariana , Suplementos Nutricionais , Lisina , Carne , Humanos , Feminino , Masculino , Estudos Transversais , Adulto , Ácido 2-Aminoadípico/sangue , Lisina/sangue , Lisina/administração & dosagem , Pessoa de Meia-Idade , Biomarcadores/sangue , Alimentos Marinhos , Adulto Jovem , Valor Nutritivo , Fatores de Tempo , Aves DomésticasRESUMO
BACKGROUND AND AIMS: The type of fat consumed in animal-based western diets, typically rich in the saturated fat palmitate, has been implicated in cardiometabolic disease risk. In contrast, the most abundant mono- and polyunsaturated fats, more typical in a vegetarian or plant-based diet, potentiate less deleterious effects. This study determined differences in plasma and urine metabolites when switching from omnivorous to vegetarian diet, including metabolites involved in fatty acid utilization. METHODS AND RESULTS: A prospective cohort of 38 European (EA) and African American (AA) omnivorous females were matched by age (25.7 ± 5.3y) and BMI (22.4 ± 1.9 kg/m2). Pre-intervention samples were collected while subjects consumed habitual animal-based diet. Changes in metabolites were assessed by ultra-high-performance liquid chromatography-tandem mass spectroscopy (Metabolon, Inc.) upon completing four days of novel vegetarian diet provided by the Vanderbilt Metabolic Kitchen. Changes in several diet-derived metabolites were observed, including increases in compounds derived from soy food metabolism along with decreases in metabolites of xanthine and histidine. Significant changes occurred in metabolites of saturated, monounsaturated and polyunsaturated fatty acids along with significant differences between EA and AA women in changes in plasma concentrations of acylcarnitines, which reflect the completeness of fatty acid oxidation (versus storage). CONCLUSION: These data suggest improvements in fatty acid metabolism (oxidation vs storage), a key factor in energy homeostasis, may be promoted rapidly by adoption of a vegetarian (plant-based) diet. Mechanistic differences in response to diet interventions must be understood to effectively provide protection against the widespread development of obesity and cardiometabolic disease in population subgroups, such as AA women.
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Dieta Saudável/etnologia , Dieta Vegetariana/etnologia , Metabolismo Energético , Ácidos Graxos/metabolismo , População Branca , Adulto , Negro ou Afro-Americano , Biomarcadores/sangue , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Ácidos Graxos/sangue , Ácidos Graxos/urina , Comportamento Alimentar/etnologia , Feminino , Humanos , Metaboloma , Metabolômica , Oxirredução , Estudos Prospectivos , Espectrometria de Massas em Tandem , Tennessee , Adulto JovemRESUMO
BACKGROUND: The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. METHODS AND RESULTS: Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy, were studied before and after 6-29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1LL). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m2) decreased in all patients (P < .0001). This this was inversely proportional to the baseline myocardial T1LL (r = -0.65; P = .02). CONCLUSION: Myocardial T1LL, in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen.
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Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/diagnóstico , Imagem Cinética por Ressonância Magnética/métodos , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Miocárdio/patologia , Remodelação Ventricular/fisiologia , Adulto , Quimioterapia Combinada , Feminino , Seguimentos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de TempoRESUMO
BACKGROUND: In Duchenne muscular dystrophy (DMD), abnormal cardiac function is typically preceded by a decade of skeletal muscle disease. Molecular reasons for differences in onset and progression of these muscle groups are unknown. Human biomarkers are lacking. METHODS: We analyzed cardiac and skeletal muscle microarrays from normal and golden retriever muscular dystrophy (GRMD) dogs (ages 6, 12, or 47+ mo) to gain insight into muscle dysfunction and to identify putative DMD biomarkers. These biomarkers were then measured using human DMD blood samples. RESULTS: We identified GRMD candidate genes that might contribute to the disparity between cardiac and skeletal muscle disease, focusing on brain-derived neurotropic factor (BDNF) and osteopontin (OPN/SPP1, hereafter indicated as SPP1). BDNF was elevated in cardiac muscle of younger GRMD but was unaltered in skeletal muscle, while SPP1 was increased only in GRMD skeletal muscle. In human DMD, circulating levels of BDNF were inversely correlated with ventricular function and fibrosis, while SPP1 levels correlated with skeletal muscle function. CONCLUSION: These results highlight gene expression patterns that could account for differences in cardiac and skeletal disease in GRMD. Most notably, animal model-derived data were translated to DMD and support use of BDNF and SPP1 as biomarkers for cardiac and skeletal muscle involvement, respectively.
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Biomarcadores/metabolismo , Coração/fisiopatologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Estudos de Casos e Controles , Estudos de Coortes , Cães , Humanos , Distrofia Muscular de Duchenne/genéticaRESUMO
BACKGROUND: Breast cancer (BC) treatments can cause heart failure (HF) in a subset of patients. ACC/AHA guidelines classify patients receiving cardiotoxic medications as stage A, a high-risk population for the development of HF. Circulating neuregulin (NRG) correlates with outcomes in stage C and D HF. We examined the levels of NRG in a BC cohort receiving cardiotoxic chemotherapy and its relationship with adverse cardiac effects during the transition from stage A to stage B or C HF. METHODS AND RESULTS: In an ongoing prospective study, a planned interim analysis of 78 BC women receiving either anthracycline (AC) or trastuzumab (Tsz) was performed. Biometric data, cardiac risk factors, and NRG levels, were collected before chemotherapy and after completion of AC therapy and/or 3 months into Tsz therapy. Cardiac function was measured by left ventricular ejection fraction (LVEF) by echocardiography at the above time points and longitudinally as standard of care. The interim cohort was predominately white with stage II BC and a median age of 50 years. A reduction of >10 absolute percentage points in LVEF was observed in 21.4% of the cohort, representing a transition from stage A to stage B or C HF. A statistically significant drop in plasma NRG was observed in women treated with AC and/or Tsz (P < .001). Additionally, baseline NRG correlated with the maximal change in LVEF. CONCLUSIONS: More than 20% of women experienced cardiac dysfunction, detected by decline in LVEF, and were reclassified as stage B or C HF. Plasma NRG levels were reduced after exposure to cardiotoxic chemotherapy, suggesting a loss in a cardioprotective growth factor. Higher baseline NRG levels were observed in those with the greatest decline in LVEF, supporting the continued investigation of NRG as a potential prognostic marker in early-stage HF.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/patologia , Neurregulinas/sangue , Adulto , Idoso , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/administração & dosagem , Biomarcadores/sangue , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Coortes , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neurregulinas/metabolismo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Volume Sistólico/efeitos dos fármacos , Taxa de Sobrevida , TrastuzumabRESUMO
Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.
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Introduction: Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. Methods: We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. Results and discussion: We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts, where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Infecções por HIV , Masculino , Humanos , Feminino , Diabetes Mellitus Tipo 2/complicações , Ácido 2-Aminoadípico , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Infecções por HIV/complicações , Infecções por HIV/epidemiologiaRESUMO
OBJECTIVE: The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear. METHODS AND RESULTS: We measured serum IGF-1 and IGFBP-3 concentrations in a sample of the Framingham Heart Study (N=3977, aged 40+/-9 years, 46% male) and evaluated their relations to cardiovascular risk factors using multivariable regression. Serum IGF-1 was inversely correlated with age, body mass index, total cholesterol, the presence of diabetes, alcohol consumption, and glomerular filtration rate (all P<0.01), whereas the ratio of IGF-1:IGFBP-3 was lower in women and inversely related to age, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and alcohol consumption (all P<0.0001). Circulating IGF-1 correlated negatively with insulin resistance (homeostatic model assessment) (r=-0.1; P<0.0001) and was lower in participants with more components of the metabolic syndrome (Adult Treatment Panel III criteria) (P<0.0001). Additive genetic factors (heritability) accounted for 43% and 39% of the variation of IGF-1 and IGFBP-3, respectively (both P<10(-27)). CONCLUSIONS: Our cross-sectional observations in a large community-based sample link lower circulating IGF-1 to greater metabolic risk burden and underscore substantial genetic influences on IGF-1 concentrations. Prospective studies are warranted to elucidate whether lower IGF-1 concentrations predict greater metabolic risk longitudinally.
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Doenças Cardiovasculares/etiologia , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Adulto , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Feminino , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Linhagem , Característica Quantitativa Herdável , Medição de Risco , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
AIMS: Growth factors play an important role in regulating vascular function. Data are limited regarding clinical and genetic correlates of endothelial growth factors and their associations with vascular function. METHODS AND RESULTS: We evaluated clinical and genetic correlates of circulating vascular endothelial growth factor A (VEGF), its soluble receptor sFlt-1, and hepatocyte growth factor (HGF) in 3754 Framingham Study participants. We also related the growth factors to measures of brachial artery function. Serum VEGF and HGF were higher and sFLt-1 was lower in women and smokers. VEGF and HGF were associated positively with body mass index; both displayed strong positive associations with the metabolic syndrome (P < 0.001) and its components. The heritabilities of VEGF, sFlt-1, and HGF were 78, 13, and 38%, respectively. VEGF and HGF were related positively to baseline brachial diameter (P < 0.01) and to baseline mean flow velocity (P < 0.001) in age- and sex-adjusted models, but the multivariable models failed to reach significance. None of the growth factors were related to flow-mediated dilation. CONCLUSION: In our community-based sample, circulating VEGF and HGF demonstrated high heritabilities and a sexual dimorphism. Increased angiogenesis and greater endothelial cell turnover may underlie associations of these growth factors with risk factors including smoking.
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Doenças Cardiovasculares/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Adulto , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/fisiopatologia , Estudos Transversais , Feminino , Fator de Crescimento de Hepatócito/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pais , Linhagem , Característica Quantitativa Herdável , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Omega-3 polyunsaturated fatty acids, specifically the fish-oil-derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as inflammation-resolving agents via their effects on adipose tissue. OBJECTIVE: We proposed to determine the effects of EPA and DHA on human adipocyte differentiation and inflammatory activation in vitro. METHODS: Primary human subcutaneous adipocytes from lean and obese subjects were treated with 100⯵M EPA and/or DHA throughout differentiation (differentiation studies) or for 72 h postdifferentiation (inflammatory studies). THP-1 monocytes were added to adipocyte wells for co-culture experiments. Subcutaneous and visceral adipose explants from obese subjects were treated for 72 h with EPA and DHA. Oil Red O staining was performed on live cells. Cells were collected for mRNA analysis by quantitative polymerase chain reaction, and media were collected for protein quantification by enzyme-linked immunosorbent assay. RESULTS: Incubation with EPA and/or DHA attenuated inflammatory response to lipopolysaccharide (LPS) and monocyte co-culture with reduction in post-LPS mRNA expression and protein levels of IL6, CCL2 and CX3CL1. Expression of inflammatory genes was also reduced in the endogenous inflammatory response in obese adipose. Both DHA and EPA reduced lipid droplet formation and lipogenic gene expression without alteration in expression of adipogenic genes or adiponectin secretion. CONCLUSIONS: EPA and DHA attenuate inflammatory activation of in vitro human adipocytes and reduce lipogenesis.
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Adipócitos/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Adipócitos/patologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Humanos , Inflamação/dietoterapia , Leucócitos/metabolismo , Gotículas Lipídicas/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Macrófagos/citologia , Obesidade/dietoterapia , Obesidade/metabolismoRESUMO
The human microbiome has been associated with health status, and risk of disease development. While the etiology of microbiome-mediated disease remains to be fully elucidated, one mechanism may be through microbial metabolism. Metabolites produced by commensal organisms, including in response to host diet, may affect host metabolic processes, with potentially protective or pathogenic consequences. We conducted multi-omic phenotyping of healthy subjects (N = 136), in order to investigate the interaction between diet, the microbiome, and the metabolome in a cross-sectional sample. We analyzed the nutrient composition of self-reported diet (3-day food records and food frequency questionnaires). We profiled the gut and oral microbiome (16S rRNA) from stool and saliva, and applied metabolomic profiling to plasma and stool samples in a subset of individuals (N = 75). We analyzed these multi-omic data to investigate the relationship between diet, the microbiome, and the gut and circulating metabolome. On a global level, we observed significant relationships, particularly between long-term diet, the gut microbiome and the metabolome. Intake of plant-derived nutrients as well as consumption of artificial sweeteners were associated with significant differences in circulating metabolites, particularly bile acids, which were dependent on gut enterotype, indicating that microbiome composition mediates the effect of diet on host physiology. Our analysis identifies dietary compounds and phytochemicals that may modulate bacterial abundance within the gut and interact with microbiome composition to alter host metabolism.
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Biomarkers are routinely used for noninvasive identification or monitoring of disease processes in clinical practice, as well as surrogate end points for drug development. There is a significant lack of data regarding biomarkers in children. An understanding of biomarker levels in a healthy pediatric cohort is essential as more studies begin to apply noninvasive biomarkers to pediatric populations. Brain-derived neurotrophic factor (BDNF) functions in neuronal survival and plasticity and is associated with exercise capacity and inflammatory disease processes. Osteopontin (OPN) plays a regulatory role in inflammation and may be a clinically useful biomarker of cardiovascular disease processes, ventricular remodeling, and skeletal muscle regeneration. This study describes our initial experience with a cohort of healthy pediatric patients and seeks to provide normal values of BDNF and OPN with correlation to age, gender, and cardiovascular and fitness measures. Serum BDNF and plasma OPN were measured using enzyme-linked immunosorbent assay in 33 healthy pediatric subjects. Subjects underwent complete cardiac evaluation, including echocardiography, exercise stress testing, and health risk assessment. The 5th-95th percentile was 5.63-37.86 ng/ml for serum BDNF and 4.9-164.9 ng/ml for plasma OPN. Plasma OPN correlated with number of days of exercise per week (r = 0.46, p = 0.008). No other correlations were significant. This study provides the initial data on serum BDNF and plasma OPN in children and begins to explore the relationships of BDNF and OPN to cardiovascular health and fitness in the pediatric population.
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BACKGROUND: Diabetic cardiomyopathy has been documented as an underlying cause of heart failure in diabetic patients. Although oxidative stress has been implicated in diabetic cardiomyopathy, much of the current evidence lacks specificity. Furthermore, studies investigating antioxidant protection with vitamin E in this unique cardiac phenomenon have yet to be performed. In the present study, we sought to determine whether vitamin E supplementation can confer cardioprotective effects against diabetic cardiomyopathy in relation to specific and quantitative markers of myocardial oxidative stress. METHODS AND RESULTS: Diabetes was induced in rats by a single injection of streptozotocin. Animals were fed either a basal diet or a diet enriched with 2000 IU of vitamin E per kilogram beginning immediately after induction of diabetes and continued for 8 weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) hemodynamic analysis. Myocardial oxidative stress was assessed by measuring the formation of 8-iso-prostaglandin F2alpha and oxidized glutathione. In the unsupplemented streptozotocin-diabetic rats, LV systolic pressure, rate of pressure increase (+dP/dt), and rate of pressure decay (-dP/dt) were depressed, whereas LV end-diastolic pressure was increased, indicating reduced LV contractility and slowing of LV relaxation. These hemodynamic alterations were accompanied by increased myocardial formation of 8-iso-prostaglandin F2alpha and oxidized glutathione. Vitamin E supplementation improved LV function and significantly attenuated myocardial 8-iso-prostaglandin F2alpha and oxidized glutathione accumulation in streptozotocin-diabetic rats. CONCLUSIONS: These findings demonstrate the usefulness of vitamin E supplementation during the early phases of type I diabetes for the prophylaxis of cardiomyopathy and subsequent heart failure.
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Cardiomiopatias/complicações , Diabetes Mellitus Tipo 1/complicações , Suplementos Nutricionais , Dinoprosta/análogos & derivados , Glutationa/metabolismo , Insuficiência Cardíaca/dietoterapia , Vitamina E/uso terapêutico , Animais , Cardiomiopatias/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Dinoprosta/metabolismo , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Técnicas Imunoenzimáticas , Masculino , Miocárdio/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Vitaminas/uso terapêuticoRESUMO
The purpose of this study was to determine the diagnostic test characteristics of serum neuregulin-1ß (NRG-1ß) for the detection of acute coronary syndrome (ACS). We recruited emergency department patients presenting with signs and symptoms prompting an evaluation for ACS. Serum troponin and neuregulin-1ß levels were compared between those who had a final discharge diagnosis of myocardial infarction (STEMI and NSTEMI) and those who did not, as well as those who more broadly had a final discharge diagnosis of ACS (STEMI, NSTEMI, and unstable angina). Of 319 study participants, 11% had evidence of myocardial infarction, and 19.7% had a final diagnosis of ACS. Patients with MI had median neuregulin levels of 0.16 ng/mL (IQR [0.16-24.54]). Compared to the median of those without MI, 1.46 ng/mL (IQR [0.16-15.02]), there was no significant difference in the distribution of results (P = 0.63). Median neuregulin levels for patients with ACS were 0.65 ng/mL (IQR [0.16-24.54]). There was no statistical significance compared to those without ACS who had a median of 1.40 ng/mL (IQR [0.16-14.19]) (P = 0.95). Neuregulin did not perform successfully as a biomarker for acute MI or ACS in the emergency department.
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Síndrome Coronariana Aguda/metabolismo , Infarto do Miocárdio/metabolismo , Neuregulina-1/sangue , Serotonina/sangue , Síndrome Coronariana Aguda/diagnóstico , Idoso , Diagnóstico Precoce , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Projetos Piloto , Isoformas de Proteínas/sangueRESUMO
Latent infection with Toxoplasma gondii is common in humans (approximately 30% of the global population) and is a significant risk factor for schizophrenia. Since prevalence of T. gondii infection is far greater than prevalence of schizophrenia (0.5-1%), genetic risk factors are likely also necessary to contribute to schizophrenia. To test this concept in an animal model, Nurr1-null heterozygous (+/-) mice and wild-type (+/+) mice were evaluate using an emergence test, activity in an open field and with a novel object, response to bobcat urine and prepulse inhibition of the acoustic startle response (PPI) prior to and 6 weeks after infection with T. gondii. In the emergence test, T. gondii infection significantly decreased the amount of time spent in the cylinder. Toxoplasma gondii infection significantly elevated open field activity in both +/+ and +/- mice but this increase was significantly exacerbated in +/- mice. T. gondii infection reduced PPI in male +/- mice but this was not statistically significant. Aversion to bobcat urine was abolished by T. gondii infection in +/+ mice. In female +/- mice, aversion to bobcat urine remained after T. gondii infection while the male +/- mice showed no aversion to bobcat urine. Antibody titers of infected mice were a critical variable associated with changes in open field activity, such that an inverted U shaped relationship existed between antibody titers and the percent change in open field activity with a significant increase in activity at low and medium antibody titers but no effect at high antibody titers. These data demonstrate that the Nurr1 +/- genotype predisposes mice to T. gondii-induced alterations in behaviors that involve dopamine neurotransmission and are associated with symptoms of schizophrenia. We propose that these alterations in murine behavior were due to further exacerbation of the altered dopamine neurotransmission in Nurr1 +/- mice.
Assuntos
Comportamento Animal , Deleção de Genes , Heterozigoto , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Toxoplasma/fisiologia , Toxoplasmose/genética , Animais , Antígenos de Protozoários/imunologia , Ansiedade/genética , Ansiedade/parasitologia , Ansiedade/fisiopatologia , Ansiedade/psicologia , Aprendizagem da Esquiva , Peso Corporal/genética , Doença Crônica/psicologia , Feminino , Genótipo , Masculino , Camundongos , Reflexo de Sobressalto/genética , Esquizofrenia/genética , Esquizofrenia/parasitologia , Esquizofrenia/fisiopatologia , Filtro Sensorial/genética , Soroconversão , Toxoplasma/imunologia , Toxoplasmose/fisiopatologia , Toxoplasmose/psicologiaRESUMO
BACKGROUND: Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. METHODS AND RESULTS: We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10(-8) in Framingham Heart Study and 8.39×10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10(-33) in Framingham Heart Study; P=2.53×10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels. CONCLUSIONS: Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.
Assuntos
Predisposição Genética para Doença , Fator de Crescimento de Hepatócito/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Receptor TIE-2/genética , Proteínas de Transporte Vesicular/genética , Adulto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Modelos GenéticosRESUMO
BACKGROUND: HER2 antagonists (anti-HER2; e.g., trastuzumab and lapatinib) are effective in treating an aggressive form of breast cancer (BC), but can cause cardiotoxicity due to the disruption in neuregulin (NRG)/HER2+ ligand receptor signalling. The recent data show that NRG-HER2 receptors located in the medulla oblongata are important regulators of vasomotor tone. Disrupting the NRG-HER2 signalling in mouse medulla results in increased sympathetic nerve output and blood pressure. We hypothesized that anti-HER2 agents would cause increased sympathetic tone with changes in plasma catecholamines and NRG. METHODS: In 15 newly diagnosed HER2+ BC patients receiving anti-HER2 agents, vital signs were measured along with supine plasma epinephrine (EPI), norepinephrine (NE), and NRG at baseline and three months. Serial echocardiography was performed. RESULTS: With three months of anti-HER2 treatment, NE increased (2.334 ± 1.294 nmol/L vs. 3.262 ± 2.103 nmol/L; p = 0.004) and NRG decreased (12.7±15.7 ng/ml vs. 10.9 ± 13.3 ng/ml; p = 0.036) with a corresponding increase in systolic blood pressure (110 ± 10 mmHg vs. 120 ± 16 mmHg, p = 0.049) and diastolic blood pressure (67 ± 14 vs. 77 ± 10, p = 0.009). There was no change, however, in EPI (0.183 ± 0.151 nmol/L vs. 0.159 ± 0.174 nmol/L; p = 0.519) or heart rate (73 ± 12 bpm vs. 77 ± 10 bpm, p = 0.146). Left ventricular ejection function declined over the follow-up period (baseline 63 ± 6% vs. follow-up 56 ± 5%). CONCLUSIONS: Anti-HER2 treatment results in increased NE, blood pressure, and decreased NRG; this suggests that the inhibition of NRGHER2 signalling leads to increased sympathoneural tone. Larger studies are needed to determine if these observations have prognostic value and may be offset with medical interventions, such as beta-blockers. CLINICAL TRIAL REGISTRATION: The study was registered with www.clinicaltrials.gov (NCT00875238).
RESUMO
AIMS: Recombinant Neuregulin (NRG)-1ß has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1ß on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1ß isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. METHODS AND RESULTS: Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. CONCLUSIONS: This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Neuregulina-1/farmacologia , Neuregulina-1/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Eletrocardiografia , Fibrose , Glucose/metabolismo , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Injeções Intravenosas , Masculino , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Miocárdio/patologia , Neuregulina-1/administração & dosagem , Neuregulina-1/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Isoformas de Proteínas/metabolismo , Proteoma/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptores Proteína Tirosina Quinases/metabolismo , Sobrevivência de Tecidos/efeitos dos fármacos , UltrassonografiaRESUMO
BACKGROUND: Visceral adiposity is associated with metabolic risk. Given that angiogenesis is a key feature of adipogenesis, variation in the association of levels of circulating vascular growth factors (and their soluble receptors) with distinct body fat compartments may explain differences in the systemic pathogenicity of regional fat depots. METHODS AND RESULTS: Four body fat compartments [visceral adipose tissue (VAT), sc adipose tissue (SAT), thoracic periaortic fat, and pericardial fat] derived from computed tomography were related to serum concentrations of vascular endothelial growth factor (VEGF), the soluble VEGF receptor (fms-like tyrosine kinase-1), hepatocyte growth factor (HGF), and angiopoietin-2 and its soluble receptor (soluble tyrosine kinase with immunoglobulin-like and EGF-like domains 2 sTie-2) in 1806 Framingham Heart Study participants (mean age 44.9 yr, 44.5% women). In multivariable models, we observed positive associations between several fat compartments and VEGF and HGF levels. The magnitude of the associations were similar for VAT, SAT, and periaortic fat. We observed effect modification by sex. A stronger association was observed between VAT and HGF levels in women; higher VAT and periaortic fat were jointly associated with higher HGF concentrations (P=0.02 and P=0.051, respectively). In women within the highest tertile of VAT, HGF levels significantly increased with higher periaortic fat (P=0.0005). CONCLUSIONS: In our large community-based sample, greater adiposity was associated with higher circulating growth factor levels in general. Additional studies are warranted to confirm the stronger association of VAT and periaortic fat with HGF in women and to examine its potential contribution to the sex-related differences in cardiometabolic risk.