Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update

The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation ofβ-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.

Importância da gordura alimentar na prevenção e no controle de distúrbios metabólicos e da doença cardiovascular

A Organização Mundial da Saúde (OMS) reiterou recentemente que o consumo de dietas inadequadas e a inatividade física estão entre os dez principais fatores de mortalidade. Diversos ensaios aleatorizados demonstram que intervenções alimentares adequadas podem diminuir ou prevenir significativamente o aparecimento de várias doenças crônicas não transmissíveis. Neste contexto, o papel da dieta vem sendo exaustivamente avaliado em estudos clínicos e epidemiológicos. Assim, já foi bem estabelecido na literatura que a quantidade e o tipo de gordura alimentar exercem influência direta sobre fatores de risco cardiovascular, tais como a concentração de lípides e de lipoproteínas plasmáticas, bem como sua associação a processos inflamatórios. Os ácidos graxos participam de complexos sistemas de sinalização intracelular, função que vem sendo bastante explorada. Os ácidos graxos poli-insaturados não somente influenciam a composição das membranas, metabolismo celular e sinais de tradução, mas também modulam a expressão de genes, regulando a atividade e a produção de diversos fatores de transcrição. A proposta deste artigo é rever tópicos relevantes referentes ao metabolismo de lípides e os relacionar a terapias nutricionais que possam contribuir para a prevenção e o tratamento de doenças associadas.

Mortalidade cardiovascular por sexo e faixa etária em São Paulo, Brasil: 1996 a 1998 e 2003 a 2005

FUNDAMENTO: O conhecimento da evolução da mortalidade cardiovascular é importante para levantar hipóteses sobre a sua ocorrência e subsidiar medidas de prevenção e controle. OBJETIVOS: Comparar a mortalidade pelo conjunto das doenças cardiovasculares e seus principais subgrupos: doença isquêmica do coração e cerebrovasculares (DIC e DCBV), no município de São Paulo, por sexo e idade, de 1996 a 1998 e 2003 a 2005. MÉTODOS: Foram usados dados de óbitos do Programa de Aprimoramento das Informações de Mortalidade para o Município (PROAIM) e estimativas populacionais da Fundação Sistema Estadual de Análise de Dados (SEADE) do Estado de São Paulo. A magnitude na mortalidade e as mudanças entre os triênios foram medidas pela descrição de coeficientes e variação percentual relativa. O modelo de regressão de Poisson foi usado também para estimar a mudança na mortalidade entre os períodos. RESULTADOS: Observou-se redução importante da mortalidade cardiovascular. Os coeficientes aumentam com a idade em ambos os sexos. Também são mais elevados na população masculina, na faixa a partir dos 70 anos. Os coeficientes de mortalidade por DIC são maiores que aqueles por DCBV, tanto nos homens como nas mulheres de 50 anos ou mais. O declínio pelo conjunto das doenças cardiovasculares foi maior em mulheres de 20 a 29 anos (-30%) e em homens de 30 a 39 anos (-26%). CONCLUSÃO: A força da intensidade da mortalidade cardiovascular diminuiu entre 1996 e 1998, a 2003 e 2005. Ainda assim há diferenças entre os grupos. Essa redução pode significar, em parte, um maior acesso aos métodos diagnósticos e terapêuticos.

Impacto da proteína-C reativa no risco cardiovascular de adolescentes

FUNDAMENTO: Vários estudos sugerem que a proteína-C reativa (PCR) se correlaciona com doença arterial coronariana em adultos. Entretanto, essa associação ainda é pouco explorada em adolescentes. OBJETIVO: Avaliar a associação entre a PCR e os fatores de risco cardiovascular em adolescentes obesos. MÉTODOS: Oitenta e quatro adolescentes (12,6 ± 1,3 anos), ambos os sexos, foram distribuídos nos grupos Eutrófico (n = 28), Sobrepeso (n = 28) e Obeso (n = 28), segundo o índice de massa corpórea (IMC). A concentração de PCR (ELISA ultrassensível), o perfil lipídico e o conteúdo de anticorpos anti-LDLox (ELISA) foram determinados após jejum de 12h. RESULTADOS: Os grupos foram semelhantes quanto a idade (p = 0,13) e sexo (p = 0,83). Colesterol total, HDL-C, CT/HDL-C e LDL-C/HDL-C apresentaram diferenças significativas entre os grupos Eutrófico e Obeso. Não houve variação significativa no conteúdo de anticorpos anti-LDLox. Os valores de PCR foram diferentes entre os três grupos (p < 0,01). PCR apresentou associação significativa com IMC (β = 2,533), CB (β = 2,645) e CC (β = 2,945), CT (β = 0,006), LDL-C (β = 0,006) e anticorpos anti-LDLox (β = 0,383) e negativa entre HDL-C (β = -0,017). CONCLUSÃO: Os resultados indicam que a PCR se associa significativamente com marcadores de risco cardiovascular em adolescentes.

Avaliação nutricional e risco cardiovascular em executivos submetidos a check-up

OBJETIVO: Avaliar estado nutricional e risco cardiovascular de executivos. MÉTODOS: Estudo transversal. Foram avaliados 329 executivos de ambos os gêneros, com idade entre 31 e 70 anos, submetidos a check-up de saúde em hospital privado do município de São Paulo. Foram mensuradas as variáveis referentes a peso, estatura e circunferência da cintura (CC) e determinado o Índice de Massa Corporal (IMC). Foram analisados pressão arterial, níveis séricos de colesterol total e frações, triacilglicerol, glicose e ácido úrico. Prática habitual de atividade física foi avaliada por meio do Questionário Internacional de Atividade Física (IPAQ) e o risco cardiovascular pelo Escore de Framingham. A análise de variância e o método de Bonferroni foram utilizados para o tratamento estatístico. RESULTADOS: Média de idade foi 44,6 anos (DP=6,8), predominando o gênero masculino (89,7%). Quanto ao estilo de vida, 17% eram tabagistas e 7,3% sedentários. Os resultados médios encontrados para os exames clínicos e bioquímicos foram: pressão arterial 117,8 x 78,6 mmHg (DP=12 x 8,3), colesterol total 200,5 mg/dL (DP=35,9), LDL-c 121,8 mg/dL (DP=29,9), HDL-c 52,2 mg/dL (DP=10,9), triacilglicerol 133,7 mg/dL (DP=76,8), glicose 96,3 mg/dL (DP=20,5) e ácido úrico 6,0 e 4,2 mg/dL (DP=1,0 e 0,9) para homens e mulheres, respectivamente. O IMC médio foi de excesso de peso (26,1kg/m²; DP=6,8). A CC média estava normal entre as mulheres (79,6cm; DP=7,3) e indicou risco elevado para doenças crônicas entre os homens (96,1cm; DP=8,9). O Risco de Framingham médio foi de 5,7%. CONCLUSÃO: Os executivos estavam com excesso de peso e apresentaram baixo risco cardiovascular.

Estudo de calibração de um questionário quantitativo de freqüência alimentar aplicado à população com diferentes níveis de risco cardiovascular

O maior entrave para o estudo da síndrome metabólica na adolescência consiste na carência de pontos de corte consolidados para tal grupo etário. O presente estudo se propôs a caracterizar os marcadores de risco para a síndrome metabólica em adolescentes do sexo feminino e verificar as possíveis correlações existentes entre variáveis analisadas. Tal estudo foi realizado com 60 adolescentes, do sexo feminino, entre 14 e 18 anos de idade. Foram analisados o índice de massa corporal e seus derivados, as circunferências da cintura (C) e quadril (Q), o percentual de gordura corporal (%G) e as dosagens plasmáticas de colesterol total (CT), frações (LDL e HDL) e glicemia de jejum. Apesar da predominância da eutrofi a (90%), encontraram-se alterações importantes: elevado percentual de gordura corporal (78,3%), níveis alterados de lipídios sangüíneos, 23,3% (CT), 15% (LDL) e 5% (HDL), glicemia de jejum alterada em 6,7%, sendo que em uma das adolescentes foi diagnosticado o diabetes Mellitus. Observaram-se correlações signifi cantes entre HDL e relação C/Q (r = -0,276; p=0,032) e LDL e %G (r = 0,296; p=0,021) e entre o número de alterações apresentadas pelas adolescentes e os valores %G (r=0,300, p=0,020); CT (r=0,536, p<0,001) e LDL (r=0,506, p<0,001). A importância de tais alterações neste grupo etário se justifi ca em função do seu signifi cado clínico, uma vez que irão predispor ao aumento das taxas de morbi-mortalidade por doenças crônicas não transmissíveis na vida adulta

Associação entre nutrientes da dieta e fatores de risco cardiovascular

O objetivo desse estudo foi avaliar a influência de nutrientes da dieta, tais como, ácidos graxos monoinsaturados (MUFA), ácidos graxos polinsaturados (PUFA) e vitamina antioxidante (a-tocoferol) sobre o risco cardiovascular. Foram coletadas informações sobre o consumo alimentar de 63 indivíduos do INCOR/SP/Brasil, por meio de três recordatórios de 24 horas e realizada a análise da composição nutricional das dietas (NutWin, versão 5.1).Após jejum de 12h, as amostras de sangue foram coletadas, e a partir do plasma foram anali sados: o per f il lipídico (métodos colorimétricos), os autoanticorpos anti-LDLox (ELISA) e o a-tocoferol (HPLC). A análise em quartis demonstrou que os fatores de risco cardiovascular (IMC, CC, Colesterol Total, HDL-c, LDL-c e a geração de autoanticorpos anti-LDLox) apresentam associação negativa com os nutrientes (MUFA e PUFA) avaliados por meio do R24h e com o a-tocoferol, identifi cado como marcador bioquímico de consumo. De acordo com os nossos resultados podemos concluir que esses nutrientes são capazes de modificar o risco para doença cardiovascular

Impacto da Proteína-C reativa no risco cardiovascular de adolescentes

Vários estudos sugerem que a proteína-C reativa (PCR) se correlaciona com doença arterial coronariana em adultos. Entretanto, essa associação ainda é pouco explorada em adolescentes. Avaliar a associação entre a PCR e os fatores de risco cardiovascular em adolescentes obesos. Oitenta e quatro adolescentes (12,6 ± 1,3 anos), ambos os sexos, foram distribuídos nos grupos Eutrófico (n = 28), Sobrepeso (n = 28) e Obeso (n = 28), segundo o índice de massa corpórea (IMC). A concentração de PCR (ELISA ultrassensível), o perfil lipídico e o conteúdo de anticorpos anti-LDLox (ELISA) foram determinados após jejum de 12h. Os grupos foram semelhantes quanto a idade (p = 0,13) e sexo (p = 0,83). Colesterol total, HDL-C, CT/HDL-C e LDL-C/HDL-C apresentaram diferenças significativas entre os grupos Eutrófico e Obeso. Não houve variação significativa no conteúdo de anticorpos anti-LDLox. Os valores de PCR foram diferentes entre os três grupos (p < 0,01). PCR apresentou associação significativa com IMC (β = 2,533), CB (β = 2,645) e CC (β = 2,945), CT (β = 0,006), LDL-C (β = 0,006) e anticorpos anti-LDLox (β = 0,383) e negativa entre HDL-C (β = -0,017). Os resultados indicam que a PCR se associa significativamente com marcadores de risco cardiovascular em adolescentes

Estimating cardiovascular risk in patients with type 2 diabetes: a national multicenter study in Brazil

According to Brazilian National Data Survey diabetes is the fifth cause for hospitalization and is one of the ten major causes of mortality in this country. Aims to stratify the estimated cardiovascular risk (eCVR) in a population of type 2 diabetics (T2DM) according to the Framingham prediction equations as well as to determine the association between eCVR with metabolic and clinical control of the disease. Methods From 2000 to 2001 a cross-sectional multicenter study was conducted in 13 public out-patients diabetes/endocrinology clinics from 8 Brazilian cities. The 10-year risk of developing coronary heart disease (CHD) was estimated by the prediction equations described by Wilson et al (Circulation 1998). LDL equations were preferably used; when patients missed LDL data we used total cholesterol equations instead. Results Data from 1382 patients (59.0% female) were analyzed. Median and inter-quartile range (IQ) of age and duration of diabetes were 57.4 (51-65) and 8.8 (3-13) years, respectively without differences according to the gender. Forty-two percent of these patients were overweight and 35.4% were obese (the prevalence of higher BMI and obesity in this T2DM group was significantly higher in women than in men; p < 0.001). The overall estimated eCVR in T2DM patients was 21.4 (13.5-31.3). The eCVR was high (> 20%) in 738 (53.4%), intermediate in 202 (14.6%) and low in 442 (32%) patients. Men [25.1(15.4-37.3)] showed a higher eCVR than women [18.8 (12.4-27.9) p < 0.001]. The most common risk factor was high LDL-cholesterol (80.8%), most frequently found in women than in men (p = 0.01). The median of risk factors present was three (2-4) without gender differences. Overall we observed that 60 (4.3%) of our patients had none, 154(11.1%) one, 310 (22.4%) two, 385 (27.9%) three, 300 (21.7%) four, 149 (10.5%) five and six, (2%) six risk factors. A higher eCVR was noted in overweight or obese patients (p = 0.01 for both groups). No association was found between eCVR with age or a specific type of diabetes treatment. A correlation was found between eCVR and duration of diabetes (p < 0.001), BMI (p < 0.001), creatinine (p < 0.001) and triglycerides levels (p < 0.001) but it was not found with HbA1c, fasting blood glucose and postprandial glucose. A higher eCVR was observed in patients with retinopathy (p < 0.001) and a tendency in patients with microalbuminuria (p = 0.06). Conclusion: our study showed that in this group of Brazilian T2DM the eCVR was correlated with the lipid profile and it was higher in patients with microvascular chronic complications. No correlation was found with glycemic control parameters. These data could explain the failure of intensive glycemic control programs aiming to reduce cardiovascular events observed in some studies.

Genetic Variants of Diabetes Risk and Incident Cardiovascular Events in Chronic Coronary Artery Disease

Objective: To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence. Methods: From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve. Results: Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non-diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610). Conclusions: Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease.

Evaluating gene by sex and age interactions on cardiovascular risk factors in Brazilian families

Background: In family studies, it is important to evaluate the impact of genes and environmental factors on traits of interest. In particular, the relative influences of both genes and the environment may vary in different strata of the population of interest, such as young and old individuals, or males and females. Methods: In this paper, extensions of the variance components model are used to evaluate heterogeneity in the genetic and environmental variance components due to the effects of sex and age (the cutoff between young and old was 43 yrs). The data analyzed were from 81 Brazilian families (1,675 individuals) of the Baependi Family Heart Study. Results: The models allowing for heterogeneity of variance components by sex suggest that genetic and environmental variances are not different in males and females for diastolic blood pressure, LDL-cholesterol, and HDL-cholesterol, independent of the covariates included in the models. However, for systolic blood pressure, fasting glucose and triglycerides, the evidence for heterogeneity was dependent on the covariates in the model. For instance, in the presence of sex and age covariates, heterogeneity in the genetic variance component was suggested for fasting glucose. But, for systolic blood pressure, there was no evidence of heterogeneity in any of the two variance components. Except for the LDL-cholesterol, models allowing for heterogeneity by age provide evidence of heterogeneity in genetic variance for triglycerides and systolic and diastolic blood pressure. There was evidence of heterogeneity in environmental variance in fasting glucose and HDL-cholesterol. Conclusions: Our results suggest that heterogeneity in trait variances should not be ignored in the design and analyses of gene-finding studies involving these traits, as it may generate additional information about gene effects, and allow the investigation of more sophisticated models such as the model including sex-specific oligogenic variance components.

Revisiting clinical trials on glycemic control and cardiovascular risk

The most relevant clinical trials, assessing the role of glycemic control in reducing cardiovascular risk, are examined. The UKPDS was the first to address this issue. More recent trials (ACCORD, ADVANCE and VADT) are controversial and evidences did not support that strict glycemic control (reflected by normal glycated hemoglobin) exclusively is sufficient to reduce cardiovascular risk in complicated individuals with long-term type 2 diabetes mellitus. Some possible reasons for controversies are included.

In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction

This work aimed to evaluate cardiac morphology/function and histological changes induced by bone marrow cells (BMCs) and cultured mesenchymal stem cells (MSCs) injected at the myocardium of spontaneously hypertensive rats (SHR) submitted to surgical coronary occlusion. Female syngeneic adult SHR, submitted (MI) or not (C) to coronary occlusion, were treated 24 h later with in situ injections of normal medium (NM), or with MSCs (MSC) or BMCs (BM) from male rats. The animals were evaluated after 1 and 30 days by echocardiography, histology of heart sections and PCR for the Y chromosome. Improved ejection fraction and reduced left ventricle infarcted area were observed in MSC rats as compared to the other experimental groups. Treated groups had significantly reduced lesion tissue score, increased capillary density and normal (not-atrophied) myocytes, as compared to NM and C groups. The survival rate was higher in C, NM and MSC groups as compared to MI and BM groups. In situ injection of both MSCs and BMCs resulted in improved cardiac morphology, in a more physiological model of myocardial infarction represented by surgical coronary occlusion of spontaneously hypertensive rats. Only treatment with MSCs, however, ameliorated left ventricle dysfunction, suggesting a positive role of these cells in heart remodeling in infarcted hypertensive subjects.

Heritability of cardiovascular risk factors in a Brazilian population: Baependi Heart Study

Background: The heritability of cardiovascular risk factors is expected to differ between populations because of the different distribution of environmental risk factors, as well as the genetic make-up of different human populations. Methods: The purpose of this analysis was to evaluate genetic and environmental influences on cardiovascular risk factor traits, using a variance component approach, by estimating the heritability of these traits in a sample of 1,666 individuals in 81 families ascertained randomly from a highly admixed population of a city in a rural area in Brazil. Results: Before adjustment for sex, age, age(2), and age x sex interaction, polygenic heritability of systolic (SBP) and diastolic (DBP) blood pressure were 15.0% and 16.4%, waist circumference 26.1%, triglycerides 25.7%, fasting glucose 32.8%, HDL-c 31.2%, total cholesterol 28.6%, LDL-c 26.3%, BMI 39.1%. Adjustment for covariates increased polygenic heritability estimates for all traits mainly systolic and diastolic blood pressure (25.9 and 26.2%, respectively), waist circumference (40.1%), and BMI (51.0%). Conclusion: Heritability estimates for cardiovascular traits in the Brazilian population are high and not significantly different from other studied worldwide populations. Mapping efforts to identify genetic loci associated with variability of these traits are warranted.

Cardiovascular response during trigeminal ganglion compression for trigeminal neuralgia according to the use of local anesthetics

There are controversies about the use of local anesthetics during balloon compression for trigeminal neuralgia (TN) as a protective factor for cardiovascular events. The objective of this study was to investigate cardiovascular parameters (blood pressure and heart rate [HR]) of patients that underwent trigeminal balloon compression with local anesthetics compared to a control group (placebo). This is a randomized controlled study; 55 patients were randomized into two groups: study (deep sedation and trigeminal block with 0.8-mL lidocaine 2%) and control group (deep sedation and trigeminal injection of 0.8-mL saline). Blood pressure and HR were measured in five distinct moments: preoperative, during puncture for local anesthesia/placebo, during puncture with the catheter, during balloon compression, and final evaluation. Statistical analysis was performed with Pearson`s chi (2) and McNemar tests and the analysis of variance for repetitive measures. The means of systolic and diastolic blood pressures (SBP and DBP, respectively) were higher in the control group when compared to the study group at the evaluation during puncture with the catheter (p < 0.001) and balloon compression (p < 0.001 and p = 0.018 for DBP and SBP, respectively). There was an increase in the HR in the control group during the procedure (p = 0.017). The use of local anesthetics during the trigeminal balloon compression for TN can have a preventive role for the risk of cardiovascular events.