RESUMO
BACKGROUND: As the population of obese and severely obese young adults grows, it is becoming increasingly important to recognize the long-term risks associated with adolescent obesity. OBJECTIVES: This study aimed to determine the association between body mass index (BMI) in young men at enlistment for military service and later risk of venous thromboembolism (VTE). METHODS: Nationwide register-based prospective cohort study of men enlisting 1969 to 2005, followed through the Swedish National Patient and Cause of Death registries. We identified 1 639 838 men (mean age, 18.3 years) free of prior venous thromboembolism, of whom 29 342 were obese (BMI 30 to <35 kg m-2 ) and 7236 severely obese (BMI ≥ 35 kg m-2 ). The participants were followed until a first registered diagnosis of VTE. RESULTS: During a median follow-up of 28 years (interquartile interval, 20 to 36 years), 11 395 cases of deep vein thrombosis and 7270 cases of pulmonary embolism were recorded. Compared with men with a BMI of 18.5 to <20 kg m-2 , men with higher BMI in young adulthood showed an incrementally increasing risk of VTE that was moderately but significantly increased already at normal BMI levels. Adolescent obese men with a BMI of 30 to 35 kg m-2 had an adjusted hazard ratio of 2.93 (95% confidence interval, 2.65 to 3.24) for VTE. Severely obese men with a BMI of ≥35 kg m-2 had a hazard ratio of 4.95 (95% confidence interval, 4.16 to 5.90). CONCLUSIONS: Men who were obese or severely obese in young adulthood had a marked increase in risk of VTE.
Assuntos
Obesidade Infantil/complicações , Tromboembolia Venosa/etiologia , Adolescente , Adulto , Índice de Massa Corporal , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade Infantil/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Adulto JovemRESUMO
Atherosclerotic plaque formation and progression are dependent on local shear stress patterns and inflammatory cytokines. Statins effectively reduce the progression of atherosclerosis and the incidence of cardiovascular events. However, the benefit of statins cannot be explained by cholesterol reduction alone. This study, investigated the non-lipid lowering effects of simvastatin and rosuvastatin on endothelial anti- and prothrombotic genes under different biomechanical and inflammatory stress conditions. Endothelial cells responded in a similar way to simvastatin and rosuvastatin. However, they were more sensitive to simvastatin. The statins had anti-inflammatory properties counteracting the TNF-α effect on the hemostatic genes studied. There was no observed synergistic effect between shear stress and simvastatin. Simvastatin had a counteracting effect on t-PA and PAI-1 compared to TNF-α and shear stress. Simvastatin blocked the TNF-α suppressive effect on thrombomodulin and eNOS, irrespective of shear stress. The strong inductive effect of TNF-α on VCAM-1 was counteracted by simvastatin and shear stress in an additive dose-response dependent way.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hemostasia/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Resistência ao Cisalhamento , Estresse Mecânico , Fator de Necrose Tumoral alfa/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Hemostasia/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Sinvastatina/farmacologia , Ativador de Plasminogênio Tecidual/genéticaRESUMO
OBJECTIVE: To identify, in a prospective study, how blood pressure levels at the age of twenty predict hypertension and cardiovascular remodelling 20 years later. METHODS: Twenty-year-old men with blood pressure (BP) elevation [systolic blood pressure (SBP) 140-160 and/or diastolic blood pressure (DBP) 85-95 mmHg; blood pressure elevation (BPE) group] or normal BP [SBP 110-130 and DBP 60-80 mmHg; normal controls (NC) group] entered the study in 1987. In 2007, follow-up was conducted including ambulatory BP, echocardiography, anthropometric and intima media thickness (IMT) measurements. RESULTS: Assessed with 24-h ambulatory BP, the prevalence of hypertension was 35/47 (74.5%) and 1/17 (5.9%) in the BPE and NC group at follow-up respectively. Twenty-four hour mean arterial pressure (MAP) increased from 86.6 (0.8) to 97.2 (1.2) (P < 0.0001), and from 83.1 (1.5) to 88.1 (1.2) mmHg (P < 0.01) from baseline to follow-up in the BPE and NC group respectively. At follow-up, left ventricular mass index (LVMI) was 122 (4) and 106 (4) g m(-1) in the BPE and NC group (unpaired t-test; P < 0.01) respectively, whilst IMT was 0.61 (0.01) and 0.57 (0.01) mm in the BPE and NC group (P < 0.05) respectively. In a logistic regression model, prevalence of hypertension was best explained by office MAP and 24-h DBP at baseline (R(2) 0.333; P < 0.05). A combined model of office MAP, body mass index and insulin levels at baseline explained 56% of LVMI at follow-up. CONCLUSIONS: BP elevation in young age predicts hypertension and adverse cardiovascular remodelling at the age of 40 years. Baseline office MAP is the best predictor of hypertension, 24-h MAP and LVMI.
Assuntos
Pressão Sanguínea/fisiologia , Hipertensão/fisiopatologia , Adulto , Antropometria , Monitorização Ambulatorial da Pressão Arterial , Artérias Carótidas/diagnóstico por imagem , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hipertensão/epidemiologia , Islândia/epidemiologia , Lipídeos/sangue , Modelos Logísticos , Masculino , Prevalência , Estudos Prospectivos , Túnica Média/diagnóstico por imagem , Ultrassonografia , Função Ventricular Esquerda/fisiologia , Adulto JovemRESUMO
Biomechanical stress modulates vascular tone, vascular remodelling and the spatial localisation of atherosclerotic plaques. Inflammatory cytokines, such as TNF-alpha, regulate expression of genes that impair the function of endothelial cells. This study investigates the combinatory effect of different biomechanical stresses and TNF-alpha on the expression of endothelial anti- and prothrombotic genes. Human umbilical vein endothelial cells were exposed to TNF-alpha and different levels of static/pulsatile tensile stress or shear stress. The response in endothelial cells to TNF-alpha was not modulated by tensile stress. However, shear stress was a more potent stimulus. Shear stress counteracted the cytokine-induced expression of VCAM-1, and the cytokine-suppressed expression of thrombomodulin and eNOS. Shear stress and TNF-alpha additively induced PAI-1, whereas shear stress blocked the cytokine effect on t-PA and u-PA. A flow profile characterized by high laminar shear stress seems to render the endothelial cell more resistant to inflammatory stress.
Assuntos
Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Estresse Mecânico , Trombose/genética , Fator de Necrose Tumoral alfa/fisiologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Inibidor 1 de Ativador de Plasminogênio/genética , Resistência ao Cisalhamento , Resistência à Tração , Ativador de Plasminogênio Tecidual/genética , Fator de Necrose Tumoral alfa/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/genéticaRESUMO
AIMS: Myocardial ischemia remains a significant perioperative complication in coronary artery disease (CAD) patients. We hypothesized that noxious stimuli during major surgery are associated with an acute release of tissue-type plasminogen activator (t-PA) into the coronary circulation, and that this response is reduced by CAD. METHODS AND RESULTS: Two patient groups, with (n=14) and without (n=8) CAD, were studied during the initial phase of heart surgery. After retrograde great cardiac vein catheterizations during closed-chest conditions, coronary arterial-venous concentration gradients of t-PA and plasminogen activator inhibitor type-1 (PAI-1) were measured together with coronary blood flow measurements, allowing derivation of coronary net release rates. Pre-surgery atrial pacing, performed to evaluate the influence of increases in heart rate (+ 40 beats/min) and coronary blood flow (+ 80 ml/min), did not significantly alter coronary net release of t-PA or PAI-1 in either patient group. Sternotomy induced a prominent increase in coronary net release of both total and active t-PA in the non-CAD group. This response was considerably reduced in the CAD group. CONCLUSIONS: This study provides the first analysis of coronary t-PA release during major surgery and demonstrates a deficient local endothelial t-PA release in patients with CAD. This suggests a reduced local fibrinolytic capacity in CAD patients, which may explain the increased risk for coronary thrombosis in this patient group.
Assuntos
Doença da Artéria Coronariana/metabolismo , Isquemia Miocárdica/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Idoso , Pressão Sanguínea , Estimulação Cardíaca Artificial/métodos , Procedimentos Cirúrgicos Cardíacos/métodos , Cateterismo de Swan-Ganz , Trombose Coronária/prevenção & controle , Vasos Coronários/metabolismo , Endotélio Vascular/metabolismo , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Several proatherothrombotic conditions are associated with enhanced levels of circulating proinflammatory cytokines, which are believed to impair endothelial fibrinolytic capacity. OBJECTIVE: This study aims at investigating how tumor necrosis factor (TNF)-alpha regulates endothelial gene expression of the key fibrinolytic enzyme tissue-type plasminogen activator (t-PA). METHODS: Cultured human umbilical vein endothelial cells were pretreated with selective inhibitors of the three major inflammatory signaling pathways activated by TNF-alpha; the nuclear factor kappa-B (NF-kappaB), the p38 mitogen-activated protein kinase (p38 MAPK), and the c-jun N-terminal kinase (JNK) pathways. Following TNF-alpha stimulation, effects on t-PA gene expression were evaluated with real-time reverse transcriptase polymerase chain reaction and interactions of nuclear proteins with potential gene regulatory elements were studied with electrophoretic mobility shift assays. RESULTS: Approximately 50% suppression of t-PA gene expression was observed after prolonged stimulation with TNF-alpha (> or =24 h). The repression was shown to be preferentially dependent on NF-kappaB activation, but also on p38 MAPK signaling. Further, we provide evidence for a TNF-alpha induced binding of NF-kappaB to the recently described kappaB site in the t-PA gene and of cyclic adenosine monophosphate response element binding protein (CREB) to the t-PA CRE-like site. CONCLUSIONS: We conclude that TNF-alpha impairs fibrinolytic capacity in vascular endothelial cells by a NF-kappaB and p38 MAPK-dependent suppression of t-PA. This mechanism sheds a light on how inflammation contributes to the pathogenesis of cardiovascular diseases.
Assuntos
Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , NF-kappa B/metabolismo , Ativador de Plasminogênio Tecidual/biossíntese , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sítios de Ligação , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Endotélio Vascular/citologia , Fibrinólise , Humanos , Inflamação , Estrutura Terciária de Proteína , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Veias Umbilicais/citologiaRESUMO
Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. SUMMARY: Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.
Assuntos
Endotélio Vascular/metabolismo , Trombose/tratamento farmacológico , Ativador de Plasminogênio Tecidual/metabolismo , Ácido Valproico/farmacologia , Animais , Aorta/metabolismo , Coagulação Sanguínea , Plaquetas/metabolismo , Inibidores Enzimáticos/farmacologia , Fibrinólise , Hemorragia , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Testes de Função Plaquetária , RNA Mensageiro/metabolismoRESUMO
OBJECTIVES: This study was designed to assess the relation of electrocardiographic (ECG) strain to increased left ventricular (LV) mass, independent of its relation to coronary heart disease (CHD). BACKGROUND: The classic ECG strain pattern, ST depression and T-wave inversion, is a marker for left ventricular hypertrophy (LVH) and adverse prognosis. However, the independence of the relation of strain to increased LV mass from its relation to CHD has not been extensively examined. METHODS: Electrocardiograms and echocardiograms were examined at study baseline in 886 hypertensive patients with ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage enrolled in the Losartan Intervention For End point (LIFE) echocardiographic substudy. Strain was defined as a downsloping convex ST segment with inverted asymmetrical T-wave opposite to the QRS axis in leads V5 and/or V6. RESULTS: Strain occurred in 15% of patients, more commonly in patients with than without evident CHD (29%, 51/175 vs. 11%, 81/711, p < 0.001). When differences in gender, race, diabetes, systolic pressure, serum creatinine and high density lipoprotein cholesterol were controlled, strain on baseline ECG was associated with greater indexed LV mass in patients with (152 +/- 33 vs. 131 +/- 32 g/m2, p < 0.001) or without CHD (131 +/- 24 vs. 119 +/- 22 g/m2, p < 0.001). In logistic regression analyses, strain was associated with an increased risk of anatomic LVH in patients with CHD (relative risk 5.14, 95% confidence interval [CI] 1.16 to 22.85, p = 0.0315), without evident CHD (relative risk 2.91, 95% CI 1.50 to 5.65, p = 0.0016), and in the overall population when CHD was taken into account (relative risk 2.98, 95% CI 1.65 to 5.38, p = 0.0003). CONCLUSIONS: When clinical evidence of CHD is accounted for, ECG strain is likely to indicate the presence of anatomic LVH. Greater LV mass and higher prevalence of LVH in patients with strain offer insights into the known association of the strain pattern with adverse outcomes.
Assuntos
Eletrocardiografia/métodos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/diagnóstico , Idoso , Doença das Coronárias/complicações , Feminino , Humanos , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Detection and quantification of differentially expressed genes requires valid and reliable references to control for error variability introduced by preparatory procedures or efficiency of reverse transcription and polymerase chain reaction (PCR) amplification conditions. So-called housekeeping genes are frequently used as endogenous standards, based on the assumption that they are constitutively expressed and independent of experimental conditions. However, if the influence of experimental stimuli is to be analyzed, it cannot a priori be assumed that their expression is unaffected by stimulation. In the present study, the authors studied the expression of different housekeeping genes in the vascular endothelium of intact conduit vessels perfused in a unique biomechanical perfusion model. Ten control gene candidates were investigated by microarray expression analysis. Further, five of these genes were systematically analyzed by real-time reverse transcriptase (RT)-PCR gene quantification and their suitability as reference genes were evaluated. On the basis of these findings, the authors suggest criteria for evaluation of endogenous control genes in vascular perfusion studies.
Assuntos
Endotélio Vascular/fisiologia , Perfilação da Expressão Gênica , Expressão Gênica , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Cordão Umbilical/fisiologia , Pesquisa Biomédica , Perfilação da Expressão Gênica/métodos , Perfilação da Expressão Gênica/normas , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Análise de Sequência com Séries de Oligonucleotídeos/normas , Perfusão , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normasRESUMO
OBJECTIVE: By using a computerized vascular perfusion model, we investigated temporal effects of sub-acute pressure elevation on vasomotor behavior and expression of endothelin-1 (ET-1) and endothelial nitric oxide synthase (eNOS) in intact human conduit vessels. METHODS: Paired umbilical veins were perfused during 1.5, 3 and 6 h under high/low intraluminal pressure (40/20 mmHg) and at identical shear stress level of 10 dyn/cm(2). ET-1 and eNOS gene and protein expression was quantified with real-time reverse-transcribed polymerase chain reaction and quantitative immunohistochemistry, respectively. RESULTS: Pressure induced differential temporal regulation patterns of ET-1 and eNOS gene expression. During the high pressure condition, eNOS mRNA was upregulated after 3 h and leveled off after 6 h of perfusion, while ET-1 mRNA was elevated after 6 h perfusion. Immunohistochemistry verified synchronal changes at the protein level. Significant vasodilation was observed after 3 h in the high-pressure system. CONCLUSION: Thus, subacute pressure elevation exerts differential effects on the endothelial eNOS/ET-1 expression, which dynamically regulate the vasomotor tone.
Assuntos
Simulação por Computador , Endotelina-1/genética , Endotélio Vascular/metabolismo , Modelos Cardiovasculares , Óxido Nítrico Sintase/genética , Resistência Vascular , Análise de Variância , Endotelina-1/análise , Endotélio Vascular/química , Expressão Gênica , Humanos , Imuno-Histoquímica , Óxido Nítrico Sintase/análise , Óxido Nítrico Sintase Tipo III , Perfusão , Pressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de TempoRESUMO
Essential hypertension is frequently associated with insulin resistance and hyperinsulinemia. In vitro, insulin has vasodilator actions, but its possible hemodynamic effect on muscular vascular beds in humans is a matter of controversy. We investigated the effects of local hyperinsulinemia on the vascular responses to norepinephrine and physiological vasodilation during mental stress in the perfused-forearm model. Nine glucose-tolerant, normotensive, nonobese men (aged 22 to 36 years) participated. Forearm perfusion studies (venous occlusion plethysmography) were performed during randomized, double-blind intrabrachial artery infusions of insulin (to raise plasma insulin 100 microU/mL) or placebo for 2 hours. A mental stress test and stepwise intra-arterial infusion of norepinephrine (6 to 1200 ng/min) were performed during each infusion. Insulin infusion increased venous plasma insulin to 98.4 microU/mL and increased net glucose uptake threefold. Insulin had a gradual vasodilator effect (P < .05 by ANOVA), and after 90 minutes blood flow was 36 percent units higher relative to the control arm than during placebo (P = .005). During mental stress, forearm blood flow increased by 81% (t test, P = .006) and 92% (P = .01) in the study arm during insulin and placebo infusions, respectively (insulin versus placebo, P = NS). An increased forearm blood flow was maintained throughout the mental stress test during insulin infusion (ANOVA, P = .03). Forearm glucose uptake increased during stress, reflecting forearm hyperperfusion since fractional glucose extraction was unaffected by stress. The increased blood flow was maintained throughout the five norepinephrine dose steps (ANOVA, P < .04).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antebraço/irrigação sanguínea , Insulina/farmacologia , Norepinefrina/farmacologia , Estresse Psicológico/fisiopatologia , Vasos Sanguíneos/efeitos dos fármacos , Método Duplo-Cego , Hemodinâmica/efeitos dos fármacos , Humanos , Hiperinsulinismo/fisiopatologia , Masculino , Placebos , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
Essential hypertension is closely related to conditions with impaired glucose tolerance and hyperinsulinemia. To evaluate a possible interaction between the sympathetic nervous system and carbohydrate ingestion on the circulatory responses to psychosocial stress, we compared the hemodynamic effects of an oral glucose challenge with those observed after placebo in 10 glucose-tolerant, normotensive young men at rest and during standardized mental stress. After glucose, resting cardiac output increased by 20% (p less than 0.05), which was mainly due to an increased heart rate (+14%; p less than 0.001). Since total peripheral resistance decreased by 13% (p less than 0.02), mean arterial pressure was unaffected by glucose. In spite of this, glucose loading was associated with a slight increase in systolic blood pressure and a gradual decrease of diastolic blood pressure. Resting forearm blood flow was unaffected by glucose. The stress response after placebo was characterized by the expected increase in cardiac output and mean arterial pressure, and an unchanged total peripheral resistance. By contrast, in the postprandial state the pressor response to stress was solely dependent on an increased systemic vascular resistance, and cardiac output was unaffected by stress. After glucose, the stress-induced muscular vasodilation in the forearm was reduced to 40% of that observed after placebo (p less than 0.01). Thus, acute carbohydrate administration has significant hemodynamic effects in humans. Furthermore, during the postprandial period there is a marked alteration of the pattern of the circulatory responses to psychosocial stress, characterized by attenuated muscular vasodilation and a rise in systemic vascular resistance.
Assuntos
Glucose/farmacologia , Hemodinâmica/efeitos dos fármacos , Estresse Psicológico/fisiopatologia , Administração Oral , Adulto , Análise de Variância , Glicemia/análise , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Catecolaminas/sangue , Epinefrina/sangue , Frequência Cardíaca/efeitos dos fármacos , Humanos , Insulina/sangue , Masculino , Norepinefrina/sangue , Volume Sistólico/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
Circulating epinephrine may facilitate neural release of norepinephrine both during and after periods of sympathoadrenal activation by stimulation of prejunctional beta-adrenergic receptors. The present study was undertaken to examine possible effects and aftereffects of epinephrine on the hemodynamic reactivity to mental stress. To this end, two strictly standardized mental stress tests were performed in 14 normotensive men during and 1 hour after double-blind infusion of epinephrine (50 ng x kg-1 x min-1) or placebo given in random order. During epinephrine infusion, the systolic pressor response to psychosocial stress was augmented (+17 versus +10 mm Hg during epinephrine and placebo, respectively; p = 0.02). This was associated with an attenuated post-stress recovery, with the result that the stress exposure induced a prolonged elevation of systolic blood pressure. Heart rate was elevated and diastolic blood pressure lowered during epinephrine infusion without any change in the reactivity to stress. One hour after the end of the epinephrine infusion resting heart rate was still maintained on a higher level independently of level of arousal, but heart rate and blood pressure responses to stress were unaffected. The findings are consistent with the hypothesis that high circulating epinephrine levels amplify pressor responses to mental stress but do not support the suggestion that short-term infusion of epinephrine causes prolonged augmentation of blood pressure responses to psychosocial stress.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Epinefrina/farmacologia , Estresse Psicológico/fisiopatologia , Adulto , Análise de Variância , Epinefrina/sangue , Humanos , Pressão Negativa da Região Corporal Inferior , Masculino , Receptores Adrenérgicos beta/fisiologiaRESUMO
Central obesity increases the risk for cardiovascular disease, but little is known about its hemodynamic effects. The aims were to investigate the influence of obesity (as defined by body mass index) and abdominal fat accumulation (as defined by the waist/hip ratio) on hemodynamics at rest and during mental stress. Invasive hemodynamic studies were performed in 20 healthy, normotensive young men (aged 18-22 years) recruited from an unbiased population sample. Their body mass index and waist/hip ratio ranged between 18.5 and 30.2 (mean 24.1) and 0.77 and 0.98 (mean 0.87), respectively. Hemodynamics were related to the two anthropometric indexes by bivariate regression analyses. Cardiac output and stroke volume were positively correlated to body mass index (p = 0.05 and p = 0.005), but inversely to waist/hip ratio (p = 0.01 and p = 0.01). Mental stress augmented the hemodynamic patterns. Total peripheral resistance during stress correlated inversely to body mass index (p = 0.02), whereas high waist/hip ratio was associated with higher systemic vascular resistance p = 0.002). The delta CO/delta MAP ratio, i.e., relative contribution of cardiac output for the stress-induced increase in mean arterial pressure, showed a strong positive association with body mass index (p = 0.004), but was inversely related to the waist/hip ratio (p = 0.002). Serum insulin correlated significantly to the stress-induced change in total peripheral resistance (r = 0.54; p = 0.02), whereas the increase in cardiac output was inversely related to insulin (r = -0.59; p = 0.007). Thus, central obesity is associated with a specific hemodynamic pattern characterized by higher total peripheral resistance, lower cardiac output, and a vasoconstrictor response to psychosocial stress.
Assuntos
Tecido Adiposo/patologia , Circulação Cerebrovascular , Obesidade/patologia , Adulto , Índice de Massa Corporal , Hemodinâmica , Humanos , Masculino , Descanso , Estresse Psicológico/fisiopatologiaRESUMO
Despite effective antihypertensive therapy, essential hypertension is still associated with considerable residual risk of cardiovascular complications. The aim of the present study was to investigate the state of the endogenous fibrinolytic system in young subjects with borderline hypertension. Thirty-nine young (age, 24 to 34 years) male subjects with borderline hypertension (systolic BP [SBP] 140 to 160 mm Hg and/or diastolic BP [DBP] 85 to 95 mm Hg) and 17 normotensive control subjects (age, 22 to 31 years; SBP 110 to 130 and DBP 60 to 80 mm Hg) were recruited from a population screening. Plasma levels of tissue-type plasminogen activator (t-PA) antigen and activity and plasminogen activator inhibitor 1 (PAI-1) antigen were determined at rest and in response to a venous occlusion test. Borderline-hypertensive subjects had metabolic and anthropometric characteristics similar to normotensive individuals. In comparison with normotensive subjects, borderline-hypertensive subjects had higher plasma concentration of t-PA antigen both at rest and after venous occlusion but similar levels of t-PA activity or PAI-1 antigen. The increase in t-PA antigen and activity in response to venous occlusion was significantly greater in borderline-hypertensive subjects than in normotensive control subjects (P < .0001 and P = .003, respectively). In stepwise regression analyses, 24-hour mean arterial pressure emerged as the single most powerful predictor of t-PA antigen levels, but body mass index was the most important determinant of t-PA activity and PAI-1 antigen. However, PAI-1 was explained by both body mass index (partial r = .48, P < .001) and 24-hour mean arterial pressure (partial r = .29, P < .05). Thus, early hypertension may be associated with significant alterations in endogenous fibrinolysis.
Assuntos
Hipertensão/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Adulto , Pressão Sanguínea , Seguimentos , Humanos , Hipertensão/fisiopatologia , Masculino , Análise de Regressão , Fatores de RiscoRESUMO
We recently discovered that patients with essential hypertension have a markedly impaired capacity for stimulated release of tissue plasminogen activator (tPA) from vascular endothelium. This defect may reduce the chance of timely spontaneous thrombolysis in case of an atherothrombotic event. We now investigated whether increased intraluminal pressure as such may depress vascular tPA release or downregulate its gene expression. Segments of human umbilical veins were studied in a new computerized vascular perfusion model under steady laminar flow conditions for 3 or 6 hours. Paired segments were perfused at high or physiological intraluminal pressure (40 versus 20 mm Hg) under identical shear stress (10 dyne/cm(2)). Quantitative immunohistochemical evaluation of cellular tPA immunoreactivity was performed on paraffin-embedded 5-microm vascular sections. tPA mRNA in endothelial cells was quantified with reverse transcription real-time TaqMan polymerase chain reaction with GAPDH as endogenous control. Secretion of tPA into perfusion medium was evaluated with SDS-PAGE and Western blotting, followed by densitometric quantification. High-pressure perfusion downregulated tPA gene expression with a 38% decrease in tPA mRNA levels (P=0.01) compared with vessels perfused under normal intraluminal pressure. tPA release into the perfusion medium was markedly suppressed by high pressure (P<0.01 ANOVA). The intracellular storage pool of tPA was reduced after 6 but not 3 hours. Thus, elevated intraluminal pressure downregulates tPA gene and protein expression and inhibits its release from the endothelium independently of shear stress. The defective capacity for stimulated tPA release that we demonstrated in patients with essential hypertension might thus be an effect of the elevated intraluminal pressure per se.
Assuntos
Ativador de Plasminogênio Tecidual/metabolismo , Veias Umbilicais/metabolismo , Pressão Sanguínea , Regulação para Baixo , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase , Estresse Mecânico , Ativador de Plasminogênio Tecidual/genética , Veias Umbilicais/patologia , Veias Umbilicais/fisiopatologiaRESUMO
Obesity may limit sensitivity of ECG voltage criteria for left ventricular hypertrophy (LVH) because of the attenuating effects of increased body mass on precordial voltages. However, obesity is associated with an increased prevalence of anatomic LVH, making more accurate ECG criteria in obese patients a clinical priority. ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria was used to select patients for the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Clinical and ECG data were available in 8417 patients (54% women; mean age, 67+/-7 years); 2519 were overweight and 1573 were obese by gender-specific body mass index criteria. Increased body mass index had significant but directionally opposite effects on ECG LVH by these 2 criteria. Compared with normal-weight patients, obese and overweight patients had lower Sokolow-Lyon voltage and a lower prevalence of ECG LVH by Sokolow-Lyon criteria (10.9% versus 16.2% versus 31.4%; P<0.001). In contrast, obese and overweight patients had higher mean values of the Cornell product and higher prevalences of ECG LVH by this criterion (75.1% versus 69.9% versus 60.7%; P<0. 001). After adjustment for age, gender, race, myocardial infarction, and diastolic and pulse pressure with the use of logistic regression analysis, increased body mass remained highly predictive of the presence of ECG LVH. Compared with normal-weight patients, obese patients had a >2-fold higher risk of ECG LVH by the Cornell product but a 4-fold lower risk of ECG LVH by Sokolow-Lyon voltage; overweight status was associated with intermediate risks, with a 151% greater likelihood of ECG LVH by the Cornell product but only 44% of the risk of LVH by Sokolow-Lyon voltage criteria compared with normal-weight individuals. Thus, Sokolow-Lyon voltage criteria underestimate the prevalence of anatomic LVH in the presence of obesity, whereas Cornell product criteria for ECG LVH appear to provide a more accurate measure of LVH in obese and overweight patients.
Assuntos
Eletrocardiografia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico , Obesidade/complicações , Idoso , Anti-Hipertensivos/uso terapêutico , Índice de Massa Corporal , Feminino , Humanos , Hipertensão/tratamento farmacológico , Losartan/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fatores de RiscoRESUMO
We have previously shown distinct effects of shear stress and pressure on transcription of several potent vascular mediators. In the present study, we tested the hypothesis that c-jun and c-fos are regulated differentially by shear and pressure. Intact human umbilical veins were perfused with various combinations of shear and pressure during 1.5, 3 and 6 h. Protein and gene expressions were assessed by immunofluorescence and real-time reverse transcription PCR, respectively. Shear stress and pressure exert differential temporal effects on c-jun and c-fos gene and protein expression, and these immediate-early gene responses appear to be cell-type specific for endothelial and smooth muscle cells.
Assuntos
Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , Genes Precoces/genética , Pressão Hidrostática , Estresse Mecânico , Endotélio Vascular/fisiologia , Imunofluorescência , Genes fos/genética , Genes jun/genética , Hemodinâmica/fisiologia , Humanos , Técnicas In Vitro , Músculo Liso/metabolismo , Especificidade de Órgãos , Perfusão , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Fatores de Tempo , Veias Umbilicais , Regulação para CimaRESUMO
Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6- and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r = 0.102, ns to r = 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.
Assuntos
Ativador de Plasminogênio Tecidual/metabolismo , Adulto , Artéria Braquial , Ritmo Circadiano , Endotélio Vascular/metabolismo , Fibrinólise , Humanos , Masculino , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/sangueRESUMO
The mechanism of ADP-mediated platelet activation has been difficult to unravel due to the large number of receptors for extracellular nucleotides (P2 receptors). mRNA levels in circulating platelets are very low, but have been shown to be translationally active. By optimizing mRNA extraction and using real time (RT)-PCR we were able to establish a protocol for highly sensitive platelet mRNA quantification in human regular blood samples. In platelets from healthy volunteers, only P2X1, P2Y1 and P2Y12 were found in significant levels, with the following order of expression: P2Y12 >> P2X1 > P2Y1. Other P2 receptors (P2Y2, P2Y4, P2Y6, P2Y11, P2Y13, P2X4, P2X7) had very low expression. As a control measurement to exclude contamination, P2 receptors in buffy coat were quantified but had a completely different profile. Incubation in vitro revealed a more rapid degradation rate for P2X1 receptor mRNA than for P2Y1 and P2Y12, indicating that the level of P2X1 may be relatively higher in newly released platelets and in megacaryocytes. In conclusion, we have developed the first protocol for quantifying mRNA expression in human platelets limiting the P2 receptor drug development targets to P2Y12, P2Y1 and P2X1. Furthermore, the method could be used to study platelet expression for any gene in human materials.