RESUMO
BACKGROUND: Multidimensional Prognostic Index (MPI), calculated on cognitive, functional, nutritional, social, pharmacological and comorbidity domains, strongly correlates with mortality in older patients. Hip fractures are a major health problem and are associated with adverse outcomes in those affected by frailty. AIM: We aimed at evaluating whether MPI is a predictor of mortality and rehospitalization in hip fracture older patients. METHODS: We investigated the associations of MPI with all-cause 3- and 6-month mortality and rehospitalization in 1259 older patients admitted for hip fracture surgical treatment and managed by an orthogeriatric team [age 85 years (65-109); male gender: 22%]. RESULTS: Overall mortality was 11,4%, 17% and 23,5% at 3, 6 and 12 months from surgery (rehospitalizations: 15, 24,5 and 35,7%). MPI was associated (p < 0.001) with 3-, 6- and 12- month mortality and readmissions; Kaplan-Meier estimate for rehospitalization and survival according to MPI risk classes confirmed these results. In multiple regression analyses these associations were independent (p < 0.05) of mortality and rehospitalization-associated factors not included in the MPI, such as gender, age and post-surgical complications. Similar MPI predictive value was observed in patients undergoing endoprosthesis or other surgeries. ROC analysis confirmed that MPI was a predictor (p < 0.001) of both 3- and 6- month mortality and rehospitalization. CONCLUSIONS: In hip fracture older patients, MPI is a strong predictor of 3-, 6- and 12- months mortality and rehospitalization, independently of surgical treatment and post-surgical complications. Therefore, MPI should be considered a valid pre-surgical tool to identify patients with higher clinical risk of adverse outcomes.
Assuntos
Fraturas do Quadril , Readmissão do Paciente , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Prognóstico , Fraturas do Quadril/cirurgia , Fraturas do Quadril/epidemiologia , Hospitalização , Comorbidade , Avaliação Geriátrica/métodos , Fatores de RiscoRESUMO
INTRODUCTION AND METHODS: Skeletal muscle mitochondrial dysfunction may cause tissue oxidative stress and consequent catabolism in chronic kidney disease (CKD), contributing to patient mortality. We investigated in 5/6-nephrectomized (Nx) rats the impact of n3-polyunsaturated fatty-acids (n3-PUFA) isocaloric partial dietary replacement on gastrocnemius muscle (Gm) mitochondrial master-regulators, ATP production, ROS generation and related muscle-catabolic derangements. RESULTS: Nx had low Gm mitochondrial nuclear respiratory factor-2 and peroxisome proliferator-activated receptor gamma coactivator-1alpha, low ATP production and higher mitochondrial fission-fusion protein ratio with ROS overproduction. n3-PUFA normalized all mitochondrial derangements and pro-oxidative tissue redox state (oxydized to total glutathione ratio). n3-PUFA also normalized Nx-induced muscle-catabolic proinflammatory cytokines, insulin resistance and low muscle weight. Human uremic serum reproduced mitochondrial derangements in C2C12 myotubes, while n3-PUFA coincubation prevented all effects. n3-PUFA also enhanced muscle mitophagy in-vivo and siRNA-mediated autophagy inhibition selectively blocked n3-PUFA-induced normalization of C2C12 mitochondrial ROS production. CONCLUSIONS: In conclusion, dietary n3-PUFA normalize mitochondrial master-regulators, ATP production and dynamics in experimental CKD. These effects occur directly in muscle cells and they normalize ROS production through enhanced mitophagy. Dietary n3-PUFA mitochondrial effects result in normalized catabolic derangements and protection from muscle wasting, with potential positive impact on patient survival.
Assuntos
Ácidos Graxos Ômega-3 , Insuficiência Renal Crônica , Trifosfato de Adenosina/metabolismo , Animais , Gorduras na Dieta/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Mitocôndrias/metabolismo , Mitofagia , Músculo Esquelético/metabolismo , Atrofia Muscular , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/metabolismoRESUMO
Growing evidence suggests that changes in muscle mass and function may further contribute to health risk assessment in individuals who are obese. As numbers for both obese and aged population subgroups are increasing worldwide, sarcopenic obesity is emerging as a relevant factor associated with higher risk for adverse events and outcomes in several clinical settings, including cancer. Recent reports showing that prevalence of sarcopenic obesity may involve up to one-third of patients with cancer despite body mass index strongly support the need for its evaluation in oncological clinical practice. In fact, in several cancer types, sarcopenic obesity is associated with poorer outcomes that include metabolic and surgical complications, longer hospitalization, physical disability, and shorter survival. Importantly, sarcopenic obesity may also have an effect on chemotherapy, as it may induce a higher risk for dose-limiting-toxicity. The aim of this review was to present an updated overview on the definition, effects, mechanisms, and clinical relevance of sarcopenia in this setting.
Assuntos
Neoplasias , Sarcopenia , Idoso , Composição Corporal , Índice de Massa Corporal , Humanos , Músculo Esquelético , Neoplasias/complicações , Neoplasias/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Sarcopenia/epidemiologiaRESUMO
BACKGROUND: Hyperosmolar dehydration (HD) is a risk factor for severe complications in hip fracture in older patients. However, evidence for recommending screening of dehydration is insufficient and its relation with frailty and mortality is unclear. We tested the hypothesis that postoperative HD is associated with frailty and increased mortality. METHODS: We recruited 625 older (>65 years) patients surgically treated for hip fracture and co-managed by an orthogeriatric team over one year in 2017. Pre- and postoperative HD (serum osmolarity > 300 mmol/L) was diagnosed. Frailty and associated mortality risk were assessed by the Multidimensional Prognostic Index (MPI). RESULTS: The prevalence of preoperative HD was 20.4%. Compared with no-HD, MPI was similar in HD patients despite higher (p < 0.05) prevalence of polypharmacy, arterial hypertension, diabetes, chronic kidney disease and heart failure. After surgery the incidence of HD decreased to 16.5%, but increased (p = 0.003) in the MPI high-risk subgroup. Postoperative HD was associated with more complications and was an independent determinant of adjusted hospital length of stay (LOS) and of 60- to 365-days mortality. CONCLUSIONS: Older frail patients with hip fracture are prone to developing postoperative HD, which independently predicts prolonged hospital LOS and mortality. Systematically screening older patients for frailty and dehydration is advisable to customize hydration management in high-risk individuals.
Assuntos
Fragilidade , Fraturas do Quadril , Idoso , Desidratação/complicações , Fragilidade/complicações , Fragilidade/diagnóstico , Fraturas do Quadril/complicações , Fraturas do Quadril/cirurgia , Humanos , Tempo de Internação , Complicações Pós-Operatórias/epidemiologia , Período Pós-OperatórioRESUMO
BACKGROUND & AIMS: Unacylated ghrelin (UnAG) modulates insulin sensitivity. Low plasma UnAG occurs in obesity and potentially contributes to obesity-associated insulin resistance. We hypothesized that improvements in insulin sensitivity in obese people induced by moderate caloric restriction (CR) may be paralleled and at least in part explained by concurrent increases in UnAG levels. METHODS: 20 general community obese people were randomly assigned to 16-week CR (n = 11) or control diet (n = 9). We investigated the impact of CR on the interaction between insulin sensitivity changes [area under the curve (AUCg) of glucose infusion to maintain euglycemia during hyperinsulinemic-euglycemic clamp] and plasma total (TotalG), acylated (AG) and Unacylated ghrelin (UnAG). Plasma pro-inflammatory tumor necrosis factor alpha (TNFα) and anti-inflammatory interleukin-10 (IL-10) were also measured since changes in inflammation may contribute to UnAG activities. RESULTS: CR reduced BMI and increased insulin sensitivity (p < 0.05). TotalG and UnAG but not AG increased in CR but not in Control (p < 0.05). Il-10 and IL-10/TNFα ratio also increased in CR (p < 0.05). Changes in UnAG were positively associated with changes in AUCg in all subjects (n = 20; p < 0.01) also after adjustment for treatment and changes in BMI and cytokines. CONCLUSIONS: Caloric restriction modifies circulating ghrelin profile with selective increase in unacylated hormone in obese individuals. The current study supports the hypothesis that higher unacylated ghrelin contributes to improvements in insulin sensitivity following diet-induced weight loss in human obesity.
Assuntos
Restrição Calórica/métodos , Grelina/sangue , Resistência à Insulina/fisiologia , Obesidade/sangue , Obesidade/dietoterapia , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Ingestão de Energia/fisiologia , Feminino , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Fator de Necrose Tumoral alfa/sangue , Redução de PesoRESUMO
Background: Skeletal muscle (SM) mitochondrial dysfunction, oxidative stress, inflammation and muscle mass loss may worsen prognosis in chronic heart failure (CHF). Diet-induced obesity may also cause SM mitochondrial dysfunction as well as oxidative stress and inflammation, but obesity per se may be paradoxically associated with high SM mass and mitochondrial adenosine triphosphate (ATP) production, as well as with enhanced survival in CHF. Methods: We investigated interactions between myocardial infarction(MI)-induced CHF and diet-induced obesity (12-wk 60% vs. standard 10% fat) in modulating gastrocnemius muscle (GM) mitochondrial ATP and tissue superoxide generation, oxidized glutathione (GSSG), cytokines and insulin signalling activation in 10-wk-old mice in the following groups: lean sham-operated, lean CHF (LCHF), obese CHF (ObCHF; all n = 8). The metabolic impact of obesity per se was investigated by pair-feeding ObCHF to standard diet with stabilized excess body weight until sacrifice at wk 8 post-MI. Results: Compared to sham, LCHF had low GM mass, paralleled by low mitochondrial ATP production and high mitochondrial reative oxygen species (ROS) production, pro-oxidative redox state, pro-inflammatory cytokine changes and low insulin signaling (p < 0.05). In contrast, excess body weight in pair-fed ObCHF was associated with high GM mass, preserved mitochondrial ATP and mitochondrial ROS production, unaltered redox state, tissue cytokines and insulin signaling (p = non significant vs. Sham, p < 0.05 vs. LCHF) despite higher superoxide generation from non-mitochondrial sources. Conclusions: CHF disrupts skeletal muscle mitochondrial function in lean rodents with low ATP and high mitochondrial ROS production, associated with tissue pro-inflammatory cytokine profile, low insulin signaling and muscle mass loss. Following CHF onset, obesity per se is associated with high skeletal muscle mass and preserved tissue ATP production, mitochondrial ROS production, redox state, cytokines and insulin signaling. These paradoxical and potentially favorable obesity-associated metabolic patterns could contribute to reported obesity-induced survival advantage in CHF.
Assuntos
Insuficiência Cardíaca/patologia , Inflamação/patologia , Mitocôndrias Musculares/patologia , Músculo Esquelético/patologia , Trifosfato de Adenosina/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal , Doença Crônica , Citocinas/metabolismo , Ingestão de Energia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Inflamação/sangue , Inflamação/complicações , Insulina/metabolismo , Masculino , Camundongos Obesos , Tamanho do Órgão , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Superóxidos/metabolismoRESUMO
Deterioration of muscle strength during cancer results in functional limitation, poor quality of life and reduced survival. The indirect effects on muscle strength of nutritional interventions based on protein and amino acid derivatives targeted at improving muscle mass are poorly documented. A scoping review was performed to examine the available evidence on the effects of proteins, amino acids and their derivatives on muscle strength in adult cancer patients. Pubmed and Scopus databases were searched to identify research articles published in the last 10 years. Fourteen studies met the inclusion criteria, showing that changes in muscle strength following protein or amino acid supplementation are generally concordant with those in muscle mass in cancer patients. Administration of both energy and proteins in the presence of reduced oral intakes results in more robust effects on both muscle strength and mass. It is not clear whether this is due to the correction of the energy deficit or to an interaction between proteins and other macronutrients. The optimal mixture, type, and dose of amino acid/protein supplementation alone or in combination with other anabolic strategies should be determined to provide the best nutritional approach in cancer.
Assuntos
Aminoácidos/administração & dosagem , Dieta Rica em Proteínas , Proteínas Alimentares/administração & dosagem , Suplementos Nutricionais , Força Muscular , Músculo Esquelético/metabolismo , Neoplasias/complicações , Fenômenos Fisiológicos da Nutrição/fisiologia , Sarcopenia/etiologia , Sarcopenia/terapia , Terapia por Exercício , Feminino , Humanos , Masculino , Músculo Esquelético/fisiopatologia , Qualidade de Vida , Sarcopenia/fisiopatologiaRESUMO
BACKGROUND: Obesity [Body Mass Index (BMI) > 30 kg/m2] is a risk factor for disease conditions enhancing hospitalization and mortality risks, but higher BMI was paradoxically reported to reduce mortality in several acute and chronic diseases. Unintentional weight loss (WL) is conversely associated with disease development and may worsen patient outcome, but the impact of weight loss and its interaction with obesity in modulating risk of death in hospitalized patients remain undefined. METHODS: We investigated the ESPEN nutritionDay database of non-critically ill hospitalized patients to assess the impact of self-reported 3-month WL (WL1:2.5-6.6%; WL2: 6.6-12.6%, WL3: >12.6%) and its interaction with BMI in modulating 30-day in-hospital mortality. Multivariate Cox regression was used to estimate hazard ratios (HR), with stable weight (WL0) as reference category. RESULTS: In 110835 nDay patients, 30-day mortality increased with increasing WL. Male gender, increasing disease severity index PANDORA score (age, nutrient intake, mobility, fluid status, cancer and main patient group) and not having had surgery also predicted 30-day mortality. HR for 30-day mortality remained significantly higher compared to WL0 for WL2 and WL3 after multiple adjustment. Adjusted HR and its increments through increasing weight loss categories were comparable in lean (BMI<25), overweight (BMI 25-30) and obese individuals (BMI>30 kg/m2). Impact of gender, PANDORA score and surgery on 30-day mortality were conversely comparable in the three BMI groups. CONCLUSIONS: These results indicate that self-reported WL could represent a relevant prognostic factor in every hospitalized patient. Overweight and obesity per se have no protective impact against WL-associated mortality.
Assuntos
Índice de Massa Corporal , Mortalidade Hospitalar , Obesidade/mortalidade , Sobrepeso/mortalidade , Redução de Peso , Idoso , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: Hip fractures are strongly associated with mortality in the elderly. Studies investigating predisposing factors have suggested a negative impact of poor nutritional, cognitive and functional status on patient survival, however their independent prognostic impact as well as their interactions remain undefined. This study aimed to determine whether poor nutritional status independently predicts 1 year post-fracture mortality after adjusting for cognitive and functional status and for other clinically relevant covariates. METHODS: 1211 surgically treated hip fracture elderly (age ≥ 65) patients consecutively admitted to the Orthopaedic Surgery Unit of the "Azienda Sanitaria Universitaria Integrata Trieste" (ASUITs), Cattinara Hospital, Trieste, Italy and managed by a dedicated orthogeriatric team. Pre-admission nutritional status was evaluated by Mini Nutritional Assessment (MNA) questionnaire, cognitive status by Short Portable Mental Status Questionnaire (SPMSQ) and functional status by Activity of Daily Living (ADL) questionnaire. All other clinical data, including comorbidities, type of surgery, post-operative complications (delirium, deep vein thrombosis, cardiovascular complications, infections, need for blood transfusions) were obtained by hospital clinical records and by mortality registry. RESULTS: Poor nutritional status (defined as MNA ≤23.5), increased cognitive and functional impairment were all associated with 3-, 6- and 12 month mortality (p < 0.001). Both cognitive and functional impairment were associated with poor nutritional status (p < 0.001). Logistic regression analysis demonstrated that the association between nutritional status and 3-, 6- and 12- month mortality was independent of age, gender, comorbidities, type of surgery and post-operative complications as well as of cognitive and functional impairment (p < 0.001). In contrast, the associations between mortality and cognitive and functional impairment were independent (p < 0.001) of demographic (age, gender) and clinical covariates but not of malnutrition. Kaplan-Meier analysis showed a lower mean survival time (p < 0.001) in patients with poor nutritional status compared with those well-nourished. CONCLUSIONS: In hip fracture elderly patients, poor nutritional status strongly predicts 1 year mortality, independently of demographic, functional, cognitive and clinical risk factors. The negative prognostic impact of functional and cognitive impairment on mortality is mediated by their association with poor nutritional status.
Assuntos
Disfunção Cognitiva , Fraturas do Quadril , Desnutrição , Estado Nutricional/fisiologia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/complicações , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/mortalidade , Feminino , Fraturas do Quadril/complicações , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/mortalidade , Humanos , Masculino , Desnutrição/complicações , Desnutrição/epidemiologia , Desnutrição/mortalidade , Avaliação Nutricional , Complicações Pós-OperatóriasRESUMO
BACKGROUND: Chronic heart failure (CHF) is associated with skeletal muscle abnormalities contributing to exercise intolerance, muscle loss, and negative impact on patient prognosis. A primary role has been proposed for mitochondrial dysfunction, which may be induced by systemic and tissue inflammation and further contribute to low insulin signalling. The acylated form of the gastric hormone ghrelin (AG) may improve mitochondrial oxidative capacity and insulin signalling in both healthy and diseased rodent models. METHODS: We investigated the impact of AG continuous subcutaneous administration (AG) by osmotic minipump (50 nmol/kg/day for 28 days) compared with placebo (P) on skeletal muscle mitochondrial enzyme activities, mitochondrial biogenesis regulators transcriptional expression and insulin signalling in a rodent post-myocardial infarction CHF model. RESULTS: No statistically significant differences (NS) were observed among the three group in cumulative food intake. Compared with sham-operated, P had low mitochondrial enzyme activities, mitochondrial biogenesis regulators transcripts, and insulin signalling activation at AKT level (P < 0.05), associated with activating nuclear translocation of pro-inflammatory transcription factor nuclear factor-κB. AG completely normalized all alterations (P < 0.05 vs P, P = NS vs sham-operated). Direct AG activities were strongly supported by in vitro C2C12 myotubes experiments showing AG-dependent stimulation of mitochondrial enzyme activities. No changes in mitochondrial parameters and insulin signalling were observed in the liver in any group. CONCLUSIONS: Sustained peripheral AG treatment with preserved food intake normalizes a CHF-induced tissue-specific cluster of skeletal muscle mitochondrial dysfunction, pro-inflammatory changes, and reduced insulin signalling. AG is therefore a potential treatment for CHF-associated muscle catabolic alterations, with potential positive impact on patient outcome.
Assuntos
Grelina/farmacologia , Insuficiência Cardíaca/metabolismo , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , Animais , Biomarcadores , Modelos Animais de Doenças , Expressão Gênica , Grelina/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/etiologia , Masculino , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Musculares/genética , NF-kappa B , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , RatosRESUMO
BACKGROUND: Systemic inflammation contributes to obesity-associated complications. The short pentraxin C-reactive protein (CRP) is a validated inflammatory marker, whereas long pentraxin-3 (PTX3) limits inflammation and is adaptively stimulated by proinflammatory cytokines in vitro. Severely obese (SO) patients (body mass index [BMI]>40] have the highest obesity-associated complications and increasingly undergo surgical treatment. SO-associated changes in plasma PTX3 and their interactions with systemic inflammation are, however, unknown. OBJECTIVE: We sought to determine potential alterations in plasma PTX3 and their associations with changes in inflammatory markers before and after weight loss induced by laparoscopic Roux-en-Y gastric bypass (LRYGB). SETTING: University hospital in Trieste, Italy. METHODS: Plasma PTX3, CRP, and cytokines, including tumor necrosis factor α and interleukin 6 were measured in (1) 24 individuals with severe, class III obesity (SO; age = 42 ± 1 yr, female/male = 18/6, BMI = 45 ± 1 kg/m(2)) before and 3, 6, and 12 months after LRYGB; and (2) age- and sex-matched normal-weight (N; n = 56, BMI = 22 ± .2 kg/m(2)) or class I obese individuals (O; n = 44, BMI = 31.2 ± .3 kg/m(2)). RESULTS: SO, but not O, had higher plasma PTX3 compared with N, associated with highest proinflammatory cytokines and CRP (P<.05 versus N-O). In all patients, plasma interleukin 6 and tumor necrosis factor α were associated positively with PTX3 (P<.05). Plasma CRP and proinflammatory cytokines declined during LRYGB-induced weight loss. In contrast, high PTX3 further increased and remained elevated (P<.05 versus basal). CONCLUSIONS: Obesity level and energy balance modulate interactions between PTX3 and systemic inflammation. Elevated PTX3 is a novel, potentially adaptive alteration associated with proinflammatory cytokines in SO. Their differential changes conversely suggest circulating PTX3 as a novel negative inflammatory marker in SO undergoing LRYGB-induced weight loss.
Assuntos
Proteína C-Reativa/metabolismo , Derivação Gástrica , Inflamação/sangue , Obesidade Mórbida/cirurgia , Componente Amiloide P Sérico/metabolismo , Redução de Peso/fisiologia , Proteínas de Fase Aguda/metabolismo , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Feminino , Humanos , Inflamação/etiologia , Masculino , Obesidade Mórbida/sangue , Obesidade Mórbida/complicaçõesRESUMO
Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.
Assuntos
Apoptose/genética , Autofagia/genética , Grelina/genética , Mitocôndrias Cardíacas/metabolismo , Infarto do Miocárdio/genética , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Dependovirus , Doxorrubicina/farmacologia , Perfilação da Expressão Gênica , Biblioteca Gênica , Técnicas de Transferência de Genes , Vetores Genéticos , Membro Posterior/irrigação sanguínea , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Isquemia/genética , Isquemia/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Mitocôndrias Cardíacas/ultraestrutura , Músculo Esquelético/irrigação sanguínea , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologiaRESUMO
OBJECTIVE: Increments in red blood cell count (RBC), hemoglobin (Hb) and hematocrit (Ht) levels are reportedly associated with higher insulin resistance (IR). Obesity may cause IR, but underlying factors remain incompletely defined, and interactions between obesity, hematological parameters and IR are incompletely understood. We therefore determined whether: 1) BMI and obesity per se are independently associated with higher RBC, hemoglobin and hematocrit; 2) hematological parameters independently predict insulin resistance in obese individuals. DESIGN AND METHODS: We investigated the associations between BMI, hematological parameters and insulin resistance as reflected by homeostasis model assessment (HOMA) in a general population cohort from the North-East Italy MoMa epidemiological study (M/Fâ=â865/971, ageâ=â49 ± 1). RESULTS: In all subjects, age-, sex- and smoking-adjusted hematological parameters were positively associated with BMI in linear regression (P<0.05), but not after adjustment for HOMA or waist circumference (WC) and potential metabolic confounders. No associations were found between hematological parameters and BMI in lean, overweight or obese subgroups. Associations between hematological parameters and HOMA were conversely independent of BMI in all subjects and in lean and overweight subgroups (P<0.01), but not in obese subjects alone. CONCLUSIONS: In a North-East Italy general population cohort, obesity per se is not independently associated with altered RBC, Hb and Ht, and the association between BMI and hematological parameters is mediated by their associations with abdominal fat and insulin resistance markers. High hematological parameters could contribute to identify insulin resistance in non-obese individual, but they do not appear to be reliable insulin resistance biomarkers in obese subjects.
Assuntos
Índice de Massa Corporal , Testes Hematológicos , Resistência à Insulina , Adolescente , Adulto , Idoso , Glicemia/metabolismo , Pressão Sanguínea , Colesterol/sangue , Contagem de Eritrócitos , Feminino , Hematócrito , Hemoglobinas/metabolismo , Homeostase , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Análise de Regressão , Triglicerídeos/sangue , Adulto JovemRESUMO
BACKGROUND: Menopause is associated with increased arterial stiffness, an independent marker of cardiovascular risk. Omega-3 polyunsaturated fatty acids (N3-PUFAs) are thought to have multiple cardiovascular benefits, including prevention of arterial stiffness. We investigated whether treatment with N3-PUFA prevents increase in arterial stiffness in ovariectomized rats, an animal model of experimental menopause. METHODS: A total of 43 Wistar rats, 2 months old, were divided into 3 groups, control, sham surgery, normal diet (CTRL, n = 15); ovariectomy, normal diet (OVX, n = 14); and ovariectomy with N3-PUFA supplementation (0.8 g/kg/d in daily gavages administration; OVX + O3, n = 14). Two months after surgery, carotid-femoral pulse wave velocity (PWV) and arterial blood pressure (BP) were measured by carotid and femoral cannulation. Aortic morphometric measurements were performed after dissection. RESULTS: Ovariectomy caused a significant increase in BP (P < .05), PWV (P < .0001), and elastic modulus (P = .001) compared to CTRL. After ovariectomy, N3-PUFA supplementation completely prevented increase in arterial stiffness (P < .0001 vs OVX) and BP (P < .05 vs OVX) and resulted in a significant increase in body weight and aortic thickness. CONCLUSIONS: In an experimental model of menopause, N3-PUFA supplementation prevents arterial stiffening and other vascular changes induced by ovariectomy. These results represent a therapeutic benefit of N3-PUFAs in prevention of postmenopausal cardiovascular disease.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Menopausa , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Pressão Arterial/efeitos dos fármacos , Peso Corporal , Doenças Cardiovasculares/etiologia , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/patologia , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/administração & dosagem , Feminino , Artéria Femoral/efeitos dos fármacos , Artéria Femoral/patologia , Ovariectomia , Análise de Onda de Pulso , Ratos , Ratos Endogâmicos WKY , Fatores de Risco , Rigidez Vascular/efeitos dos fármacosRESUMO
Menopause is associated with endothelial dysfunction and oxidative stress. In this condition, reduced n-3 polyunsaturated fatty acids (n-3 PUFAs) contribute to cardiovascular disease. We investigated whether treatment with n-3 PUFA reverses endothelial dysfunction and oxidative stress in experimental menopause. Thirty female rats underwent either sham-surgery or bilateral ovariectomy or bilateral ovariectomy+oral n-3 PUFA (0.8 g kg(-1) day(-1) for 2 months). Ovariectomy caused endothelial dysfunction to acetylcholine, which was reversed by superoxide scavenger Tiron. Erythrocyte membrane lipid composition was characterized by reduced n-3 PUFA total content and omega-3 index, and by concomitant increase in n-6:n-3 PUFA ratio. Ovariectomy-related oxidative stress, demonstrated by both enhanced superoxide production and 3-nitrotyrosine expression in aorta, was associated with increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX-4 protein expression. Endothelial nitric oxide synthase (eNOS) functional inhibition by l-NG-nitroarginine methyl ester, protein expression and activity did not change. In ovariectomized rats, treatment with n-3 PUFA increased n-3 PUFA total content and omega-3 index and decreased n-6:n-3 PUFA ratio in erythrocyte membrane, reversed vascular oxidative stress, endothelial dysfunction, aortic 3-nitrotyrosine and markedly lowered NOX-4 protein expression; eNOS protein expression also increased, paralleled by reversal of inhibitory binding to Caveolin-1, while ex-vivo functional inhibition and NOS synthesis were unchanged. These findings demonstrate in vivo a therapeutic benefit of n-3 PUFA on menopause-associated endothelial dysfunction by reversal of alterations in membrane lipid composition induced by ovariectomy and by reduction of vascular oxidative stress. In this setting they also identify NOX-4 as a potential target to reduce oxidative stress-mediated vascular complications.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Ácidos Graxos Ômega-3/farmacologia , Menopausa/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sal Dissódico do Ácido 1,2-Di-Hidroxibenzeno-3,5 Dissulfônico/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Caveolina 1/metabolismo , Modelos Animais de Doenças , Feminino , Sequestradores de Radicais Livres/farmacologia , Lipídeos de Membrana/química , Lipídeos de Membrana/metabolismo , Menopausa/fisiologia , NADPH Oxidase 4 , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Ratos , Ratos Wistar , Superóxidos/metabolismo , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVE: Oxidative stress and inflammation characterize hemodialysis (HD) and are associated with malnutrition, cardiovascular disease, and poor clinical outcome. p66(shc) stimulates oxidative stress and atherogenesis. The objective of the present study was to assess p66(shc) expression levels in HD and their associations with inflammatory and oxidative stress markers. DESIGN: p66(shc) messenger ribonucleic acid (mRNA) was compared with systemic oxidative stress and inflammation markers in control subjects and patients on HD before and after a single HD session in a cross-sectional analysis. SETTING: Outpatient hemodialysis unit. PATIENTS: The study included stable HD patients (n = 21, men/women: 18/3) who were on HD 3 times per week for a minimum of 8 weeks; age-matched control subjects (n = 22, men/women:17/5). MAIN OUTCOME MEASURE: mRNA levels of p66(shc), tumor necrosis factor α (TNF-α), and pentraxin 3 (PTX3), p66(shc) protein levels in white blood cells, lipid peroxidation (in the form of plasma thiobarbituric acid-reactive substance [TBARS]) and serum C-reactive protein. RESULTS: In patients on dialysis, of the p66(shc), TNF-α, and PTX3 mRNAs, p66(shc) protein levels were higher (P < .05) than in control subjects, as well as plasma TBARS and C-reactive protein (P < .05). p66(shc) mRNA directly correlated with TBARS (r = 0.69, P = .0005) and with TNF-α mRNA (r = 0.63, P = .003). These associations were confirmed in the whole study population (TBARS: r = 0.541, P = .0003; TNF-α: r = 0.581, P < .0001), whereas in the control group only the positive association between p66(shc) and TNF-α was detected. TNF-α was directly correlated with PTX3 both in HD patients (r = 0.72, P = .0005) and in the whole study group (r = 0.678, P < .0001). The dialysis session affected neither p66(shc) and TNF-α mRNA nor p66(shc) protein expression, whereas it further increased (P = .002) PTX3 mRNA. As compared with predialysis levels, TBARS were reduced (P < .05) after dialysis. In these conditions, p66(shc) remained directly correlated with TNF-α (r = 0.901, P < .0001). CONCLUSIONS: Increased p66(shc) gene expression correlates with TNF-α mRNA and with levels of markers of oxidative stress in HD. We suggest a novel link between HD-associated inflammation and p66(shc) gene expression contributing to systemic oxidative stress.