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Nutr Metab Cardiovasc Dis ; 18(5): 349-56, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17935958


BACKGROUND AND AIM: The aim of the present study was to investigate endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives (offspring) of diabetic subjects and to explore the relationship with the metabolic syndrome and its components. METHODS AND RESULTS: Forty-five healthy normotensive normoglycemic subjects (aged 18-42 years), 29 first-degree relatives of diabetic subjects (FDR) and 16 with no parental history of type 2 diabetes mellitus were studied. Endothelial function was measured as flow-mediated dilation of the brachial artery (FMD) and arterial stiffness as carotid-femoral pulse wave velocity (PWV). Insulin resistance was calculated by homeostasis model assessment (HOMA). Plasma levels of inflammation markers (hsCRP, TNF-alpha, IL-1beta, CD40L, VCAM, and ICAM) were evaluated. Normotensive normoglycemic FDR presented a 33% lower flow-mediated dilation than the control group (9.8+/-5.2 vs. 16.2+/-7.6%, p<0.01). FMD was reduced in FDR, with or without insulin resistance, whereas arterial stiffness was significantly increased only in FDR with insulin resistance. To investigate the role of FDR status independently of altered components of the metabolic syndrome, subjects with no altered components of the metabolic syndrome were compared according to their FDR status: FDR subjects with no altered components of the metabolic syndrome presented a blunted endothelial function (lower FMD: 11.2+/-1.6 vs. 16.8+/-2.0%, p<0.05) and stiffer large arteries (higher PWV: 9.6+/-0.3 vs. 8.8+/-0.3m/s, p<0.05) than controls. CONCLUSION: Normoglycemic first-degree relatives of diabetic subjects have blunted endothelial function and increased stiffness of the large arteries. These alterations are already present at a very young age, before any alteration in glycemic control or blood pressure values can be detected, and are independent of the presence of the metabolic syndrome and its altered components.

Artérias/fisiopatologia , Glicemia/genética , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Endotélio Vascular/fisiopatologia , Síndrome Metabólica/genética , Vasodilatação , Adulto , Pressão Sanguínea/genética , Artéria Braquial/fisiopatologia , Doenças Cardiovasculares/fisiopatologia , Artérias Carótidas/fisiopatologia , Estudos de Casos e Controles , Criança , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Elasticidade , Feminino , Artéria Femoral/fisiopatologia , Humanos , Mediadores da Inflamação/sangue , Resistência à Insulina/genética , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , Linhagem
Metabolism ; 56(3): 413-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17292732


Endothelial dysfunction, insulin resistance, and elevated levels of circulating proinflammatory markers are among the earliest detectable abnormalities in people at risk for atherosclerosis. Accelerated atherosclerosis is a leading contributor to morbidity and mortality in type 2 diabetes mellitus, a complex genetic disorder. Therefore, we hypothesized that normoglycemic offspring of patients with type 2 diabetes mellitus (NOPD) may have impaired vascular and metabolic function related to an enhanced proinflammatory state. We compared NOPD (n = 51) with matched healthy control subjects without family history of diabetes (n = 35). Flow- and nitroglycerin-mediated brachial artery vasodilation were assessed by ultrasound to evaluate endothelium-dependent and -independent vascular function. Each subject also underwent an oral glucose tolerance test to evaluate metabolic function. Fasting levels of plasma adiponectin and circulating markers of inflammation (high-sensitivity C-reactive protein, CD40 ligand, interleukin 1beta, tumor necrosis factor alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule) were measured. Both NOPD and the control group had fasting glucose and insulin levels well within the reference range. However, results from oral glucose tolerance test and quantitative insulin sensitivity check index revealed that NOPD were insulin resistant with significantly impaired flow- and nitroglycerin-mediated dilation compared with the control group. Adiponectin levels were lower, whereas many circulating markers of inflammation were higher, in NOPD compared with the control group. Normoglycemic offspring of patients with type 2 diabetes mellitus have impaired vascular and metabolic function accompanied by an enhanced proinflammatory state that may contribute to their increased risk of diabetes and its vascular complications.

Artéria Braquial/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/sangue , Adulto , Proteína C-Reativa/análise , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Resistência à Insulina , Molécula 1 de Adesão Intercelular/sangue , Interleucina-1beta/sangue , Masculino , Fator de Necrose Tumoral alfa/sangue , Molécula 1 de Adesão de Célula Vascular/sangue
Am J Pathol ; 169(6): 1913-24, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17148657


Randomized clinical trials have demonstrated that the increased intake of omega-3 polyunsaturated fatty acids significantly reduces the risk of ischemic cardiovascular disease, but no investigations have been performed in hereditary cardiomyopathies with diffusely damaged myocardium. In the present study, delta-sarcoglycan-null cardiomyopathic hamsters were fed from weaning to death with an alpha-linolenic acid (ALA)-enriched versus standard diet. Results demonstrated a great accumulation of ALA and eicosapentaenoic acid and an increased eicosapentaenoic/arachidonic acid ratio in cardiomyopathic hamster hearts, correlating with the preservation of myocardial structure and function. In fact, ALA administration preserved plasmalemma and mitochondrial membrane integrity, thus maintaining proper cell/extracellular matrix contacts and signaling, as well as a normal gene expression profile (myosin heavy chain isoforms, atrial natriuretic peptide, transforming growth factor-beta1) and a limited extension of fibrotic areas within ALA-fed cardiomyopathic hearts. Consequently, hemodynamic indexes were safeguarded, and more than 60% of ALA-fed animals were still alive (mean survival time, 293+/-141.8 days) when all those fed with standard diet were deceased (mean survival time, 175.9+/-56 days). Therefore, the clinically evident beneficial effects of omega-3 polyunsaturated fatty acids are mainly related to preservation of myocardium structure and function and the attenuation of myocardial fibrosis.

Cardiomegalia/dietoterapia , Cardiomiopatias/dietoterapia , Gorduras Insaturadas na Dieta/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Ácido alfa-Linoleico/uso terapêutico , Animais , Cardiomiopatias/prevenção & controle , Cricetinae , Modelos Animais de Doenças , Fibrose Endomiocárdica/patologia , Fibrose Endomiocárdica/prevenção & controle , Ácidos Graxos/sangue , Longevidade , Contração Miocárdica
J Gene Med ; 6(9): 992-1002, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15352072


BACKGROUND: In mouse models of retinopathy of prematurity (ROP) inhibitors of vascular endothelial growth factor (VEGF) functions administered systemically completely block retinal neovascularization. In contrast, selective ocular VEGF depletion has achieved an approx. 50% inhibition of retinal neovascular growth. It is unclear whether a more complete inhibition of new blood vessel development can be obtained with an anti-VEGF therapy localized to the eye. Therefore, the objective of the present study was to determine the effect of local anti-VEGF therapy in a different animal model which closely mimics human ROP. METHODS: Rats were exposed to alternating cycles of high and low levels of oxygen for 14 days immediately after birth; thereafter, they were intravitreally injected with an adenoviral vector expressing a secreted form of the VEGF receptor flt-1 (Ad.sflt), which acts by sequestering VEGF. Contralateral eyes were injected with the control vector carrying the reporter gene expressing beta-galactosidase (Ad.betaGal). RESULTS: At the peak of retinal neovascular growth, i.e. post-natal day 21 (P21), we observed up to 97.5% decrease in retinal neovascularization in animals injected with Ad.sflt. At the end of observation (P28), no significant difference in retinal vessel number was detected in both oxygen-injured and normoxic Ad.sflt-treated retinas compared with untreated or Ad.betaGal-treated retinas. CONCLUSION: Adenoviral-mediated sflt-1 gene transfer induces a near-complete inhibition of ischemia-induced retinal neovascularization in rats without affecting pre-existing retinal vessels.

Terapia Genética/métodos , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/terapia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Adenoviridae/genética , Animais , Modelos Animais de Doenças , Vetores Genéticos/uso terapêutico , Humanos , Recém-Nascido , Ratos , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Corpo Vítreo/metabolismo
J Endovasc Ther ; 9(1): 90-7, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11958331


PURPOSE: To test the hypothesis that D-dimer (D-D), a cross-linked fibrin degradation product of an ongoing thrombotic event, could be a marker for incomplete aneurysm exclusion after endovascular abdominal aortic aneurysm (AAA) repair. METHODS: In a multicenter study, 83 venous blood samples were collected from 74 AAA endograft patients and controls. Twenty subjects who were >6 months postimplantation and had evidence of an endoleak and/or an unmodified or increasing AAA sac diameter formed the test group. Controls were 10 nondiseased subjects >65 years old, 18 AAA surgical candidates, and 26 postoperative endograft patients with no endoleak and a shrinking aneurysm. Blood samples were analyzed for D-D through a latex turbidimetric immunoassay. The endograft patients were stratified into 5 clinical groups for analysis: no endoleak and decreasing sac diameter, no endoleak and increasing/unchanged sac diameter, type II endoleak and decreasing sac diameter, type II endoleak and increasing/unchanged sac diameter, and type I endoleak. RESULTS: Individual D-D values were highly variable, but differences among clinical groups were statistically significant (p < 0.0001). D-D values did not vary significantly between patients with stable, untreated AAAs and age-matched controls (238 +/- 180 ng/mL versus 421 +/- 400 ng/mL, p > 0.05). Median D-D values increased at 4 days postoperatively (963 ng/mL versus 382 ng/mL, p > 0.05) and did not vary thereafter if there was no endoleak and the aneurysm sac decreased. D-D mean values were higher in patients with type I endoleak (1931 +/- 924 ng/mL, p < 0.005) and those with unchanged/increasing sac diameters (1272 +/- 728 ng/mL) than in cases with decreasing diameters (median 638 +/- 238 ng/mL) despite the presence of endoleak (p < 0.0005). CONCLUSIONS: Elevated D-D may prove to be a useful marker for fixation problems after endovascular AAA repair and may help rule out type I endoleak, thus excluding patients from unnecessary invasive tests.

Aneurisma da Aorta Abdominal/cirurgia , Implante de Prótese Vascular/efeitos adversos , Prótese Vascular , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Complicações Pós-Operatórias/sangue , Falha de Prótese , Angiografia , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Implante de Prótese Vascular/métodos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/diagnóstico , Probabilidade , Radioimunoensaio , Valores de Referência , Sensibilidade e Especificidade , Estatísticas não Paramétricas