RESUMO
BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.
Assuntos
Mutação , Recidiva Local de Neoplasia/diagnóstico , Neoplasias/diagnóstico , Adulto , Biomarcadores Tumorais/genética , Criança , Bases de Dados Genéticas , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Medicina de Precisão/métodos , Estudos ProspectivosRESUMO
OBJECTIVES: The objective of this report is to investigate the feasibility of collecting patient-reported outcomes (PROs) via e-questionnaires delivered to patients with chronic inflammatory diseases (CIDs). METHODS: Consecutive outpatients with a confirmed diagnosis of systemic lupus erythematosus, primary Sjögren's syndrome or inflammatory bowel disease were followed at two medical departments. Patients received monthly e-mails containing the SF36, Hospital Anxiety and Depression scale and an analogue symptom scale over a six-month period. Participation rate, socio-demographic characteristics and patients' satisfaction were analysed. RESULTS: A total of 128 patients were included (79% female; mean age: 42 ± 12 years). Eighty-two per cent of questionnaires were returned. The monthly participation rate ranged from 89% to 77%, with a six-month attrition rate of 13%. The mean completion rate of questionnaires was 98%. Factors significantly associated with increased answer rate were: married/couple status, greater number of children at home and previous participation in online surveys. The main reasons for non-response were: 'too busy to participate' (35%) and 'away from home Internet access' (31%). Overall, 68% of the participants found the study convenient and 96% agreed to continue at a monthly or bimonthly frequency. CONCLUSION: Online home self-assessment of PROs was feasible in the setting of CIDs. Patients were satisfied and willing to continue the survey. The Internet allows immediate and sophisticated presentation of PROs to clinicians. Future studies are warranted to determine how PRO monitoring may contribute to routine care in CIDs and other diseases.
Assuntos
Inflamação/diagnóstico , Cooperação do Paciente , Adulto , Doença Crônica , Estudos de Viabilidade , Feminino , Humanos , Inflamação/patologia , Doenças Inflamatórias Intestinais/diagnóstico , Internet , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Participação do Paciente , Satisfação do Paciente , Qualidade de Vida , Síndrome de Sjogren/diagnóstico , Inquéritos e QuestionáriosRESUMO
Colorectal cancer (CRC) is the third most common cancer worldwide. Colorectal cancer incidence differs widely among different geographic regions. In addition to mutational changes, epigenetic mechanisms also play important roles in the pathogenesis of CRCs. O6-methylguanine-DNA methyltransferase (O(6)-MGMT) is a DNA repair protein and in the absence of MGMT activity, G-to-A transition may accumulate in the specific genes such as K-ras and p53. To identify which CpG sites are critical for its downregulation, we analyzed the methylation status of the MGMT gene promoter in two sites in CRC patients. Then we compared the frequency of their methylation changes with the results of our previously reported K-ras gene mutation, APC2 and p16 methylation. MGMT methylation was examined in 92 tumor samples. A methylation specific PCR (MSP) method was performed for two loci of MGMT gene which described as MGMT-A and MGMT-B. The prevalence of MGMT-A, and MGMT-B methylation was 49/91 (53.8%), and 83/92 (90.2%), respectively. We detected high frequency of MGMT-B but not MGMT-A methylation in tumor tissues with APC2 methylation. Our results showed that MGMT-B methylation is significantly associated with K-ras gene mutation rather than MGMT-A (p = 0.04). Simultaneously, an inverse correlation was found between p16 and MGMT-B methylation simultaneously (p = 0.02). Our study indicated that hypermethylation of the specific locus near the MGMT start codon is critical for cancer progression. MGMT-B assessment that is associated with K-ras mutation can have a prognostic value in patients with CRC.
Assuntos
Neoplasias Colorretais/genética , Metilação de DNA , O(6)-Metilguanina-DNA Metiltransferase/genética , Regiões Promotoras Genéticas , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments. PATIENTS AND METHODS: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted. RESULTS: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis. CONCLUSION: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.
Assuntos
Inibidores de Checkpoint Imunológico , Segunda Neoplasia Primária , Humanos , Incidência , Segunda Neoplasia Primária/epidemiologiaRESUMO
Background: Peritoneal carcinomatosis (pcm) in metastatic pancreatic ductal adenocarcinomas (mpdac) is frequently encountered in day-to-day practice, but rarely addressed in the literature. The objective of the present study was to describe the management and outcome of patients diagnosed with pcm. Methods: Data for all consecutive patients with mpdac treated in our centre between 1 January 2014 and 31 August 2015 were analyzed retrospectively. Computed tomography imaging was centrally reviewed by a dedicated radiologist to determine the date of pcm diagnosis. Results: The analysis included 48 patients. Median age in the group was 61 years, and 41 patients had an Eastern Cooperative Oncology Group performance status (ecog ps) of 0-1. All patients presented with pcm either synchronously (group 1) or metachronously (group 2). Those groups differed significantly by baseline ecog ps and neutrophil-to-lymphocyte ratio (nlr), with ecog ps being poorer and nlr being higher in group 1. In addition to pcm, the main sites of metastasis were liver (62.5%) and lungs (31.3%). First-line chemotherapy in 36 patients (75%) was folfirinox (fluorouracil-irinotecan-leucovorin-oxaliplatin). The median overall survival for the entire population was 10.81 months [95% confidence interval (ci): 7.16 months to 14.16 months]; it was 13.17 months (95% ci: 5.9 months to 15.4 months) for patients treated with folfirinox. Median overall survival was 7.13 months (95% ci: 4.24 months to 10.41 months) for patients in group 1 and 14.34 months (95% ci: 9.79 months to 19.91 months) for patients in group 2, p = 0.1296. Conclusions: Compared with other metastatic sites, synchronous pcm seems to be a poor prognostic factor. It could be more frequently associated with a poor ecog ps and a nlr greater than 5 in this group of patients. In patients with mpdac and pcm, either synchronous or metachronous, folfirinox remains an efficient regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/diagnóstico por imagem , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Peritoneais/diagnóstico por imagem , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Mental stress has been shown to impair endothelium-dependent vasodilation (EDV) in the human forearm. The aim of this study was to investigate if this response could be blunted by local infusions of beta-blockade (propranolol), alpha-blockade (phentolamine), or neurogenic blockade. Thirty-one young healthy volunteers underwent forearm blood flow (FBF) measurements, using venous occlusion plethysmography, during local intra-arterial infusions of metacholine (MCh; inducing EDV) and sodium nitroprussid (SNP; inducing endothelial-independent vasodilation [EIDV]), respectively. These measurements were repeated during a 5-min mental arithmetic stress test without (n = 8) or with concomitant local infusion of propranolol (n = 7) or phentolamine (n = 8) in the forearm or during axillary plexus blockade (n = 8). An index of endothelial vasodilatory function (EFI) was calculated as the EDV to EIDV ratio. Mental stress impaired EDV significantly (p < .05), and as a result, EFI was significantly reduced (p = .02). This effect on EFI could be blocked by propranolol and neurogenic blockade but not by phentolamine (p < .05). Thus, impairment of endothelial vasodilatory function induced by mental stress could be blocked by beta-adrenergic, but not alpha-adrenergic, receptor blockade.
Assuntos
Antagonistas Adrenérgicos alfa/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Endotélio Vascular/fisiopatologia , Nitroprussiato/administração & dosagem , Fentolamina/administração & dosagem , Propranolol/administração & dosagem , Estresse Fisiológico/fisiopatologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , Adulto , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Feminino , Humanos , MasculinoRESUMO
The fatty acid (FA) composition of the serum lipids has been associated with cardiovascular disease (CVD). As an attenuated endothelium-dependent vasodilation (EDV) has been suggested as an early marker of atherosclerosis, we investigated the relationships between the proportion of FA in serum lipids (cholesterol esters and phospholipids) together with the levels of serum LDL- and HDL-cholesterol and triglycerides and EDV, as well as endothelium-independent vasodilation (EIDV). Fifty-six healthy subjects (31 men and 25 women), aged between 20 and 69 years, underwent measurements of forearm blood flow (FBF) at rest and during local infusion of 2 and 4 microg/min of metacholine (Mch, evaluating EDV), 5 and 10 microg/min of sodium nitroprusside (SNP, evaluating endothelium-independent vasodilation, EIDV) using venous occlusion plethysmography. An index of endothelial function was calculated as the ratio between EDV and EIDV. The proportion of palmitic (16:0) and palmitoleic (16:1) acids were inversely related (r=-0.35 and -0.35, P<0.01 for both), while linoleic acid (18:2 n6) and the HDL-cholesterol concentration were positively related (r=0.35 and 0.36, P<0.01 for both) to the endothelial function index. In multiple regression analysis also including age and gender, palmitoleic acid and HDL-cholesterol were significant independent predictors of endothelial function. Alfa-linolenic acid (18:3 n3) was positively correlated to both EDV and EIDV (r=0.40 and 0.43, P<0.01 for both), indicating a protective effect of this essential FA on vasodilation in general. It is concluded that the FA composition of serum lipids, partly reflecting the composition of dietary fat and previously associated with the development of CVD, was associated with endothelial function in apparently healthy subjects.
Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Endotélio Vascular/metabolismo , Ácidos Graxos/sangue , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologia , Vasodilatadores/administração & dosagem , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Estudos Transversais , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Infusões Intravenosas , Modelos Lineares , Masculino , Cloreto de Metacolina/administração & dosagem , Pessoa de Meia-Idade , Nitroprussiato/administração & dosagem , Pletismografia , Radioimunoensaio , Valores de Referência , Análise de Regressão , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.
Assuntos
Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Selectina E/sangue , Endotélio Vascular/imunologia , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão de Célula Vascular/sangue , Vasodilatação/imunologia , Adulto , Idoso , Artéria Carótida Primitiva/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Túnica Íntima/anatomia & histologia , Túnica Íntima/imunologiaRESUMO
The present study aimed to investigate the influence of the angiotensin-converting enzyme (ACE)-inhibitor captopril and the Ca-antagonist nifedipine on endothelium-dependent vasodilation (EDV) in the forearm of hypertensive patients. Twenty-three middle-aged untreated hypertensive patients underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium-nitroprusside (SNP, evaluating EIDV), before and 1 h after intake of either captopril (25 mg) or nifedipine (10 mg) in a randomised, double-blind fashion. A matched normotensive control group was investigated at baseline conditions only. Five of the hypertensives were also evaluated after 3 months of treatment with captopril 25 mg twice daily in an open pilot study. First, the vasodilation induced by methacholine (MCh), but not SNP, was significantly attenuated in the hypertensive patients compared to the normotensive controls (P < 0.001 at MCh 4 microg/min). Second, although the two drugs induced a similar decline in blood pressure (BP) 1 h after administration (-11 to 10 mm Hg/-8 to 7 mm Hg), captopril significantly potentiated the vasodilator response to MCh (+32+/-13%, MCh 4 micr og/min, P < 0.01) but not SNP, while nifedipine did not significantly alter the response to either MCh or SNP. The improvement in vasodilator response to MCh induced by captopril was closely related to the reduction in BP (r = 0.72, P < 0.01). Third, in the pilot study, 3 months of captopril treatment induced a significant potentiation of the vasodilator response to MCh (+34+/-17%, MCh 4 microg/min, P < 0.05) in parallel with a significant BP reduction (-22+/-24/13+/-13 mm Hg, P < 0.05), while the response to SNP was unchanged. In conclusion, the present study confirmed that essential hypertension is associated with a defect in EDV. Furthermore, an improvement in EDV was seen in hypertensive patients shortly after administration of captopril, but not nifedipine. In addition, a significant beneficial effect on EDV was seen in a small pilot study during long-term treatment with captopril.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Captopril/farmacologia , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Nifedipino/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Artérias/fisiopatologia , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Captopril/uso terapêutico , Método Duplo-Cego , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Feminino , Antebraço/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Nifedipino/uso terapêutico , Vasodilatadores/uso terapêuticoRESUMO
Insulin-mediated vasodilation has been suggested to be of importance for glucose uptake during normoglycemic hyperinsulinemia. If this also is valid after an ordinary mixed meal remains to be evaluated. Forearm blood flow (FBF) and forearm glucose uptake change (evaluated by venous occlusion plethysmography) and glucose arteriovenous differences were evaluated over 120 minutes in 10 healthy volunteers following an ordinary mixed meal (700-900 kcal, 34% of energy from fat). Fasting arterial glucose level was 4.9+/-0.9 mmol/l, and the maximum glucose level was reached 30 minutes after the start of ingestion (6.6+/-0.8 mmol/l, p<0.0001). Plasma insulin levels were increased four-fold. FBF increased rapidly within 20 minutes after the start of ingestion and reached its maximum after 50 minutes (94% higher than baseline level, p<0.01). After 2 hours FBF was still substantially elevated (75% above baseline level, p<0.01). Forearm glucose uptake increased fivefold already after 20 minutes ( p<0.01). During the 2 hours, the increase in FBF contributed to 41% of the forearm glucose uptake ( p<0.05). The present study showed that the increase in FBF seen after an ordinary mixed meal is important for the change in forearm glucose uptake. These results support the view that modulation of limb blood flow is a determinant of glucose uptake.
Assuntos
Glicemia/metabolismo , Antebraço/irrigação sanguínea , Glucose/metabolismo , Fluxo Sanguíneo Regional/fisiologia , Adulto , Pressão Sanguínea , Ácidos Graxos não Esterificados/sangue , Humanos , Insulina/sangue , Cinética , Consumo de Oxigênio , Pletismografia , Período Pós-Prandial , Valores de Referência , Fatores de Tempo , Triglicerídeos/sangueRESUMO
Insulin is known to increase blood flow in parallel to glucose uptake in skeletal muscle. However, it is not known if an increase in blood flow by itself is associated with an increase in glucose uptake in the absence of hyperinsulinemia. To investigate further this matter, the effect of increased blood flow on forearm glucose uptake was studied in the fasting state during intra-arterial infusions of two different vasodilators, metacholine and nitroprusside, in 19 hypertensive subjects. Both metacholine (4 microg/min) and nitroprusside (10 microg/min) increased resting forearm blood flow, measured by venous occlusion plethysmography, to a similar degree (180 % and 170 %, respectively, p<0.0001 for both). However, metacholine infusion increased the forearm glucose uptake from 2.0+/-0.9 (S.D.) during rest to 5.5+/-3.0 umol/min/100 ml tissue (p<0.0001), while no significant change in glucose uptake was seen during nitroprusside infusion (2.3+/-1.4 micromol/min/100 ml tissue). In conclusion, vasodilatation induced by metacholine, but not by nitroprusside, increased glucose uptake in the forearm of hypertensive patients. Thus, an increase in forearm blood flow does not necessarily improve glucose uptake in the forearm during the fasting state.
Assuntos
Glicemia/metabolismo , Antebraço/irrigação sanguínea , Cloreto de Metacolina/farmacologia , Nitroprussiato/farmacologia , Vasodilatadores/farmacologia , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Jejum , Humanos , Hipertensão/fisiopatologia , Cinética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Consumo de OxigênioRESUMO
Ascites, in 20% of cases, is not linked to liver cirrhosis. The pathophysiology is most often different. The understanding of these pathophysiological mechanisms can lead to etiologic diagnosis. The diagnostic approach is mainly based on the biological study of ascites, especially protein concentration and albumin gradient between serum and ascites. In Western countries, tumors and heart diseases are the predominant causes, while developing countries are mainly concerned by infectious diseases, among which tuberculosis is the leading cause. Other uncommon causes must be recognized, as ascites may be the presenting feature of the disease. Their knowledge will facilitate the therapeutic approach.
Assuntos
Ascite/diagnóstico , Ascite/etiologia , Ascite/fisiopatologia , Distrofias Hereditárias da Córnea/complicações , Surdez/complicações , Endometriose/complicações , Eosinofilia/complicações , Feminino , Humanos , Hipotireoidismo/complicações , Ictiose Lamelar/complicações , Infecções/complicações , Hepatopatias/complicações , Lúpus Eritematoso Sistêmico/complicações , Desnutrição/complicações , Neoplasias/complicações , Síndrome Nefrótica/complicações , Síndrome de Hiperestimulação Ovariana/complicações , Enteropatias Perdedoras de Proteínas/complicações , Radioterapia/efeitos adversos , Albumina Sérica/análise , Disfunção Ventricular Direita/complicaçõesRESUMO
Mental stress has been shown to induce myocardial ischemia in people with coronary heart disease (CHD), both in the laboratory and in daily life. In order to investigate the role of the endothelium in the regulation of blood flow during stress, the endothelium-dependent (EDV) and endothelium-independent (EIDV) vasodilation was examined in the forearms of healthy people during a mental arithmetic test (MAT), a cold pressor test (CP) and an isometric handgrip test (ISO). A total of 10 young healthy volunteers (four men and six women, aged 20-25 years) underwent measurements of forearm vascular resistance (FVR) during local intraarterial infusions of methacholine (MCh; inducing EDV) and sodium nitroprusside (SNP; inducing EIDV) at rest and during the different forms of stress by the use of venous occlusion plethysmography. MAT induced a significant increase in FVR during MCh infusion (4 microg/min, from 3.5 +/- 0.7 at rest to 4.2 +/- 1.4 mmHg/ml per min per 100 ml tissue during MAT; p < 0.01), while FVR during SNP infusion was unchanged by MAT. CP induced a significant increase in FVR during infusions with both MCh and SNP compared to resting levels (p < 0.01 for both), while ISO induced a significant increase in FVR during MCh infusion (p < 0.05) and a smaller increase in FVR during SNP infusion. When the SNP to MCh FVR ratio was used as an index of endothelial function, only MAT impaired endothelial function significantly (p < 0.01). In conclusion, mental stress induced by an arithmetic task selectively opposed EDV in the forearms of young healthy people, while cold pressor and isometric handgrip tests induced a more general attenuation in vasodilatation.
Assuntos
Endotélio Vascular/fisiopatologia , Estresse Psicológico/fisiopatologia , Vasodilatação/fisiologia , Adulto , Temperatura Baixa , Teste de Esforço , Feminino , Antebraço/irrigação sanguínea , Força da Mão/fisiologia , Hemodinâmica/fisiologia , Humanos , Masculino , Estresse Psicológico/sangue , Pensamento/fisiologia , Resistência Vascular/fisiologiaRESUMO
Smoking is a major risk factor for coronary and peripheral vascular disease. This study was designed to investigate the short-term effects of smoking and nicotine gum on endothelium-dependent (EDV) and -independent (EIDV) vasodilation in the forearm of young habitual smokers. In 10 subjects, forearm blood flow (FBF) during local infusion of metacholine (4 microg/min, evaluating EDV) and sodium nitroprusside (10 microg/min, evaluating EIDV) was assessed before and at 10 min (early phase) and 30-50 min (plateau phase) after the initiation of smoking, using forearm venous occlusion plethysmography. Six subjects underwent similar measurements of FBF before and 30 min after chewing a nicotine gum (4 mg). As a change in blood pressure was expected, forearm vascular resistance (FVR) was used to calculate EDV and EIDV. FVR during metacholine infusion increased from 4.6 +/- 1.4 SD to 5.9 +/- 2.1 mm Hg/ml/min/100 ml tissue during the early and to 5.0 +/- 1.6 mm Hg/ml/min/100 ml tissue at the plateau phase of smoking (p < 0.01 for both vs. baseline) and from 4.5 +/- 1.6 to 5.2 +/- 1.6 mm Hg/ml/min/100 ml tissue after chewing the nicotine gum (p < 0.01). No significant changes in EIDV were seen after smoking or the nicotine gum. When all data were analyzed together, plasma nicotine levels and blood pressure were both independent predictors of endothelial function (p < 0.001 for both). In conclusion, cigarette smoking induced a dose-dependent attenuation in EDV, being maximal shortly after initiation of smoking and persisting up to 30-50 min. Nicotine chewing gum induced a similar impairment in EDV.
Assuntos
Goma de Mascar , Endotélio Vascular/efeitos dos fármacos , Antebraço/irrigação sanguínea , Nicotina/farmacologia , Fumar , Vasodilatação/efeitos dos fármacos , Adulto , Análise de Variância , Interações Medicamentosas , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Cloreto de Metacolina/farmacologia , Nicotina/administração & dosagem , Nicotina/sangue , Nitroprussiato/farmacologia , Parassimpatomiméticos/farmacologia , Vasodilatadores/farmacologiaRESUMO
OBJECTIVES: A progressive decline in endothelium-dependent vasodilation (EDV) in the human forearm with age has previously been reported. The aim of this study was to evaluate the interplay between age, gender and metabolic factors on EDV in healthy subjects in a population-based study. SETTING: Tertiary university hospital. SUBJECTS AND DESIGN: Thirty-six healthy men and 30 women, aged 20-69 years, underwent measurements of forearm blood flow (FBF) at rest and during local infusions of 2 and 4 microg min-1 of metacholine (evaluating EDV) and 5 and 10 microg min-1 of sodium nitroprusside (evaluating endothelium-independent vasodilation, EIDV) and during reactive hyperaemia by venous occlusion plethysmography. RESULTS: Age was inversely related to EDV (r = - 0.41, P < 0.05 in men; r = - 0.61, P < 0.01 in women) and maximal FBF during reactive hyperaemia in both men and women. EIDV was significantly related to age in an inverse way in women only. EDV was more pronounced in females than in males before menopause (48 +/- 3 SD years, 635 +/- 186 vs. 502 +/- 269% in males, P < 0.05), but similar in women and men thereafter (374 +/- 141 vs. 370 +/- 185% in men). The slope of the regression line for the relationship between age and EDV was flatter in premenopausal than in postmenopausal women (- 2.3 vs. - 6.4), whilst this slope was similar in younger and older men (- 5.5 vs. - 5.3). In multiple regression analysis, fasting blood glucose levels and the waist/hip ratio remained the only significant predictors of EDV in men (P < 0.01 for both), whilst age was the only significant independent predictor of EDV in women (P < 0.01). CONCLUSION: The interplay between age and metabolic factors as determinants of endothelial function is different in healthy men and women.
Assuntos
Envelhecimento/fisiologia , Endotélio Vascular/metabolismo , Vasodilatação/fisiologia , Adulto , Idoso , Envelhecimento/metabolismo , Análise de Variância , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Feminino , Antebraço/irrigação sanguínea , Humanos , Hiperemia/fisiopatologia , Masculino , Cloreto de Metacolina , Pessoa de Meia-Idade , Nitroprussiato , Parassimpatomiméticos , Pletismografia/métodos , Valores de Referência , Caracteres Sexuais , Vasodilatação/efeitos dos fármacos , VasodilatadoresRESUMO
The present study, involving 56 healthy subjects from a health screening, was undertaken to address some methodological questions regarding the measurement of endothelial function using local intra-arterial infusions of metacholine (2 and 5 micrograms min-1) to evaluate endothelium-dependent vasodilatation, and sodium nitroprusside (SNP, 5 and 10 micrograms min-1) to evaluate endothelium-independent vasodilatation. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. The ratio of FBF during the highest dose of metacholine to FBF during the highest dose of SNP was used as an index of endothelial function. In 10 young volunteers the procedure was repeated after 2 h and again after 3 weeks in order to study short-term and long-term reproducibility of the method. Neither the vasodilatatory response to metacholine (r = 0.006) nor that to SNP (r = 0.08) was related to resting FBF. Neither the circumference nor the length of the arm was related to endothelial function (r = 0.01-0.11), as evaluated by the FBF on metacholine to nitroprusside ratio (mean 1.3 +/- 0.3 SD). The use of a wrist cuff to exclude hand circulation, or not, did not influence the evaluation of endothelial function significantly. Maximal FBF after 3 min of arterial occlusion of the forearm was significantly related to blood flow during both metacholine (r = 0.53, P < 0.01) and nitroprusside infusion (r = 0.36, P < 0.05), but not to the FBF on metacholine to nitroprusside ratio (r = 0.01). The short-term and long-term reproducibility of FBF during vasodilatation with metacholine and SNP was good (r = 0.89-0.97, P < 0.001), while the individual measurements for resting FBF were less reproducible when repeated after 3 weeks (r = 0.34). In conclusion, endothelial function was not related to resting FBF, nor to the arm circumference or length. No major difference was seen whether endothelial function was evaluated with or without exclusion of the hand circulation. Maximal FBF during reactive hyperaemia was not related to endothelial function.
Assuntos
Endotélio Vascular/fisiologia , Antebraço/irrigação sanguínea , Vasodilatação/fisiologia , Adulto , Estudos de Avaliação como Assunto , Feminino , Humanos , Hiperemia/fisiopatologia , Ligadura , Masculino , Cloreto de Metacolina/administração & dosagem , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Nitroprussiato/administração & dosagem , Parassimpatomiméticos/administração & dosagem , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Reprodutibilidade dos Testes , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem , PunhoRESUMO
To investigate the relationship between left ventricular hypertrophy (LVH) and endothelium-dependent vasodilation (EDV), 30 untreated hypertensive patients, 18 treated hypertensives (53 +/- 7 years, all males) and 26 age-and sex-matched healthy normotensive controls, underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). Forearm blood flow was measured by venous occlusion plethysmography and LVH was measured by echocardiography. The reduction in forearm vascular resistance during MCh infusion (4 microg/min) was significantly smaller in the hypertensive patients with LVH when compared to those without LVH, both in the untreated (-61 +/- 12%, n = 19 vs -72 +/- 4%, n = 11, p < 0.01) and in the treated group (-60 +/- 15%, n = 11 vs -75 +/- 5%, n = 7, p < 0.01). Thereby, EDV was significantly impaired only in the hypertensive patients with LVH when compared to controls (-77 +/- 7% at MCh 4 microg/min, p < 0.001). EIDV was not significantly different between patients with and without LVH and controls. In conclusion, the presence of LVH was related to endothelial dysfunction, both in untreated and treated hypertensive patients, suggesting either a role for endothelial function in the development of LVH, or that a dysfunctional endothelium and LVH are coexisting markers of a more severe hypertensive disease.
Assuntos
Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Vasodilatação/fisiologia , Adulto , Fatores Etários , Análise de Variância , Ecocardiografia , Endotélio Vascular/fisiopatologia , Antebraço/irrigação sanguínea , Humanos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/complicações , Masculino , Análise por Pareamento , Cloreto de Metacolina/administração & dosagem , Cloreto de Metacolina/farmacologia , Pessoa de Meia-Idade , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Pletismografia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fluxo Sanguíneo Regional/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
This study was designed to evaluate the effects of an ordinary mixed meal on endothelium-dependent vasodilation. Ten young healthy volunteers were given a mixed meal (minced meat sauce with rice, 900 kcal, 34% of the energy content was fat). In the fasting state, at 60 and 120 min after the start of the meal, endothelium-dependent vasodilation and endothelium-independent vasodilation were evaluated by local infusion of metacholine (4 microg min (-1)) and sodium nitroprusside (10 microg min (-1)) in the brachial artery. Blood flow in the forearm was measured using venous occlusion plethysmography. Endothelium-dependent vasodilation decreased from 15.4 +/- 3.3 (mean +/- SD) at fasting to 13.7 +/- 3.5 mL min (-1) (100 mL tissue)-1 (P < 0.01) 60 min after feeding, but had returned to the fasting level at 120 min. At 60 min, but not in the fasting state, the serum level of free fatty acids was inversely related to endothelium-dependent vasodilation (r=-0.74, P < 0.05), although no significant net changes in FFA levels were seen. Endothelium-independent vasodilation was not affected by the mixed meal. No similar attenuations in endothelium-dependent vasodilation were seen during control meals. In conclusion, an ordinary mixed meal transiently attenuated endothelium-dependent vasodilation. Free fatty acids may be involved in this effect on endothelial function.
Assuntos
Ingestão de Alimentos/fisiologia , Alimentos , Vasodilatação/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Química Clínica , Colina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Jejum/fisiologia , Jejum/psicologia , Ácidos Graxos não Esterificados/sangue , Feminino , Privação de Alimentos/fisiologia , Antebraço/irrigação sanguínea , Humanos , Masculino , Nitroprussiato/farmacologia , Pletismografia , Triglicerídeos/sangue , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND: Our aim was to test the hypothesis that genes encoding components in the renin-angiotensin system influence endothelial vasodilatory function. METHODS: In 59 apparently healthy, normotensive individuals, endothelium-dependent vasodilation (EDV) and endothelial-independent vasodilation (EIDV) was evaluated by infusing metacholine and sodium nitroprusside into the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography. The ACE insertion (I)/deletion (D) polymorphism, the T174M and M235T angiotensinogen restriction fragments length polymorphisms, the angiotensin II receptor type 1 (AT1R) A1166C, and the aldosterone synthase gene (CYP11B2) C-344T polymorphisms were analysed. RESULTS: When analysing the ACE, the two angiotensinogen and the aldosterone synthase CYP11B2 genotypes independently, no significant association with endothelial vasodilatory function was found. However, a significant reduction in endothelium-dependent vasodilation was observed in the subjects (n=9) with the ACE D allele and the angiotensinogen T174M genotype (P<0.05). Subjects with the AT1R genotype AC showed a reduction in both EDV (P=0.05) and EIDV (P=0.04) when compared with those with the AA genotype. CONCLUSIONS: The subjects with the ACE D allele in combination with the angiotensinogen T174M genotype are associated with a reduced EDV. This together with the observation that the AC AT1R genotype is associated with a reduction in both EDV and EIDV, supports the hypothesis that endothelial vasodilatory function is influenced by genes in the renin-angiotensinogen system.
Assuntos
Endotélio Vascular/fisiologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Sistema Renina-Angiotensina/genética , Adulto , Idoso , Citocromo P-450 CYP11B2/genética , Feminino , Deleção de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Nitroprussiato/administração & dosagem , Nitroprussiato/farmacologia , Polimorfismo de Fragmento de Restrição , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/genéticaRESUMO
Endothelial function is important for local vascular regulation and an abnormal endothelium-dependent vasodilatation (EDV) has been observed in subjects with essential hypertension. As ambulatory blood pressure (ABP) is more closely related to target organ damage than office blood pressure, this study investigated also if 24-h ABP is more closely related to an impaired EDV than office blood pressure recordings. In a group of 25 untreated patients with essential hypertension and an age- and sex-matched control group (n = 21) endothelial function was evaluated by measurements of forearm blood flow (FBF) during local intra-arterial infusions of metacholine (evaluating EDV) and sodium nitroprusside (evaluating endothelium independent vasodilation, EIDV). FBF was measured with venous occlusion plethysmography. Both office mean artery pressure (MAP; r= -0.57, p < 0.001) and 24-h ABP (r = 0.40, p < 0.01) were related to the endothelial vasodilator function (EDV to EIDV ratio) in an inverse way, but ABP was not superior to office blood pressure recordings. Within the hypertensive group, pronounced white-coat effect (office minus daytime ABP) was associated with a reduced,EDV (r= 0.41, p < 0.05). The degree of night-time decline in blood pressure ("dipping") showed no correlation to EDV. In conclusion, the finding that ABP was no more closely related to the endothelial vasodilator function than office blood pressure recordings might be due to an increased mental alertness affecting EDV in some hypertensive subjects, as suggested by the finding of a reduced EDV in those with a pronounced white-coat effect.