Variações genéticas do metabolismo da homocisteína como biomarcadores de risco cardiovascular em mulheres com antecedentes de doença hipertensiva da grávida

Tese de mestrado, Doenças Metabólicas e Comportamento Alimentar, Faculdade de Medicina, Universidade de Lisboa, 2013

Homocystéinémie, apports en vitamines B et facteurs de risque cardiométabolique au Bénin, Afrique

L'hyperhomoscystéinémie (HHcy) est considérée comme un facteur indépendant de risque cardio-métabolique. Notre travail avait pour objectifs : 1) de déterminer la prévalence de l’HHcy au Bénin; 2) d’étudier sa relation avec les apports de vitamines B12, B9, B6 et B2, la consommation d’alcool, l’âge, le sexe et le niveau socioéconomique (NSE); 3) de vérifier son association avec les facteurs classiques de risque cardio-métabolique. Un total de 541 sujets apparemment en santé et vivant dans trois zones du Bénin ont été étudiés. L’Hcy sérique a été analysée par ELISA. Des rappels de 24h ont servi à évaluer les apports nutritifs. L’obésité et l’hypertension ont été définies selon l’OMS, la dyslipidémie et la dysglycémie selon la NCEP-ATPIII. Les autres données ont été récoltées par questionnaire. La prévalence de l’HHcy était élevée : 52,2% chez les hommes et de 24,7% chez les femmes. Dans les modèles multivariés, l’Hcy était positivement associée à la consommation de bière locale chez les hommes; chez les femmes, elle était associée négativement à l'apport de vitamine B12. L’Hcy était positivement associée à la tension artérielle, au taux de LDL-cholestérol et au cholestérol total chez les hommes, mais seulement avec le rapport cholestérol total/HDL-cholestérol (CT/HDL-c) chez les femmes. Les femmes présentant une HHcy étaient au moins deux fois plus susceptibles de présenter une hypertension ou un rapport CT/HDL-c élevé que celles dont l’Hcy était normale. Un apport suffisant en B12 ainsi qu’une consommation prudente de boissons alcoolisées pourraient réduire l'HHcy et donc contribuer à réduire le risque cardio-métabolique de cette population du sud du Bénin.

Búsqueda de selección en el polimorfismo 677C>T (c.665C>T) del gen de la metilentetrahidrofolato reductasa (MTHFR) en una población Colombiana

Se realizó un estudio genético – poblacional en dos grupos etarios de población colombiana con la finalidad de evaluar las diferencias genéticas relacionadas con el polimorfismo MTHFR 677CT en busca de eventos genéticos que soporten la persistencia de este polimorfismo en la especie humana debido que este ha sido asociado con múltiples enfermedades. De esta manera se genotipificaron los individuos, se analizaron los genotipos, frecuencias alélicas y se realizaron diferentes pruebas genéticas-poblacionales. Contrario a lo observado en poblaciones Colombianas revisadas se identificó la ausencia del Equilibrio Hardy-Weinberg en el grupo de los niños y estructuras poblacionales entre los adultos lo que sugiere diferentes historias demográficas y culturales entre estos dos grupos poblacionales al tiempo, lo que soporta la hipótesis de un evento de selección sobre el polimorfismo en nuestra población. De igual manera nuestros datos fueron analizados junto con estudios previos a nivel nacional y mundial lo cual sustenta que el posible evento selectivo es debido a que el aporte de ácido fólico se ha incrementado durante las últimas dos décadas como consecuencia de las campañas de fortificación de las harinas y suplementación a las embarazadas con ácido fólico, por lo tanto aquí se propone un modelo de selección que se ajusta a los datos encontrados en este trabajo se establece una relación entre los patrones nutricionales de la especie humana a través de la historia que explica las diferencias en frecuencias de este polimorfismo a nivel espacial y temporal.  

Homocysteine Thiolactone Induces Cardiac Dysfunction: Role of Oxidative Stress

This study investigates the cardiac functioning in male Wistar rats after treatments with methionine and homocysteine thiolactone (HcyT). The rats were distributed into 3 groups and treated for 8 weeks. Group I was the control (CO) group, given water, group II was treated with methionine, and group III with HcyT (100 mg/kg). Morphometric and functional cardiac parameters were evaluated by echocardiography. Superoxide dismutase (SOD), catalase, and glutathione S-transferase activities, chemiluminescence, thiobarbituric acid reactive substances, and immunocontent were measured in the myocardium. Hyperhomocysteinemia was observed in rats submitted to the both treatments. The results showed diastolic function was compromised in HcyT group, seen by the increase of E/A (peak velocity of early (E) and late (A) diastolic filling) ratio, decrease in deceleration time of E wave and left ventricular isovolumic relaxation time. Myocardial performance index was increased in HcyT group and was found associated with increased SOD immunocontent. HcyT group demonstrated an increase in SOD, catalase, and glutatione S-transferase activity, and chemiluminescence and thiobarbituric acid reactive substances. Overall, these results indicated that HcyT induces a cardiac dysfunction and could be associated with oxidative stress increase in the myocardium.

Homocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of rats

Hyperhomocysteinemia has been related to various diseases, including homocystinuria, neurodegenerative and hepatic diseases. In the present study we initially investigated the effect of chronic homocysteine administration on some parameters of oxidative stress, named total radical-trapping antioxidant potential, total antioxidant reactivity, catalase activity, chemiluminescence, thiobarbituric acid-reactive substances, and total thiol content in liver of rats. We also performed histological analysis, evaluating steatosis, inflammatory infiltration, fibrosis, and glycogen/glycoprotein content in liver tissue sections from hyperhomocysteinemic rats. Finally, we evaluated the activities of aminotransferases in liver and plasma of hyperhomocysteinemic rats. Wistar rats received daily subcutaneous injection of Hcy from their 6th to their 28th day of life. Twelve hours after the last injection the rats were sacrificed, liver and plasma were collected. Hyperhomocysteinemia decreased antioxidant defenses and total thiol content, and increased lipid peroxidation in liver of rats, characterizing a reliable oxidative stress. Histological analysis indicated the presence of inflammatory infiltrate, fibrosis and reduced content of glycogen/glycoprotein in liver tissue sections from hyperhomocysteinemic rats. Aminotransferases activities were not altered by homocysteine. Our data showed a consistent profile of liver injury elicited by homocysteine, which could contribute to explain, at least in part, the mechanisms involved in human liver diseases associated to hyperhomocysteinemia. (C) 2009 ISDN. Published by Elsevier Ltd. All rights reserved.

Níveis de homocisteína e desempenho cognitivo em uma amostra populacional de idosos da cidade do Natal-RN

The imprecision of the frontier that separates those cognitive deficits inherent to the human physiological aging process from those which represent the early signs of nervous system degenerative pathologies ,very prevalent among the elderly, has brought attention to the need of studies aiming to establish clinical and/or laboratorial criteria to allow this differentiation. Elderly people living in poor and developing countries are frequently exposed to precarious socioeconomic conditions which facilitate the development of an array of pathologies which have metabolic and nutritional dysfunctions as the established or proposed etiological agents. The levels of certain micronutrients, such as the vitamins B12 and B9 (folic acid), and of some intermediary metabolites, such as homocysteine are being thought of as etiological factors and/or as biological markers of a group of alterations which affect the normal functioning of the nervous system with important reflexes upon cognitive performance. This study aims to investigate the influence of homocysteine, B12 vitamin and folic acid levels on the cognitive performance of the low income elderly population. This transversal study took place in Natal, Rio Grande do Norte State, Brazil, and involved 205 dwelling elderly people, users of the Programa de Saúde da Família, a public healthcare program, maintained by the city s health authorities. A multidimensional questionnaire was used to assess the socio-demographic aspects and the overall health and nutrition conditions. The cognitive performance was measured by the use of the Portuguese version of the Mini Mental State Exam (MMSE). The serum levels of homocysteine, B12 vitamin and folic acid were determined by chemiluminescence. The association between the socio-demographic and serum levels of Hcy, B12 vitamin and folic acid was determined by multiple linear regression. Serum levels higher than 13.5 μmol/l, indicative of hyperhomocysteinemia (HHcy), were found on 25.4% of the sample, being more prevalent in men (p<0.05). Deficitary levels of folic acid (<5ng/mol) and of B12 vitamin (<193 pg/ml) were found on 3.9% and 10.2% of the sample respectively. A negative correlation was found between cognitive performance with both age and HHcy and a positive correlation was found between cognitive performance and schooling. The isolated HHcy R2 values were an explanation to only 4% of the variance of the MMSE scores. However, when associated with schooling and age, this model explains about 25% of this association

Tratamento dietético da hiper-homocisteinemia na doença arterial periférica

A homocisteína está envolvida na gênese da aterosclerose e, assim, é considerada um importante e prevalente fator de risco na doença arterial periférica. O estado nutricional vitamínico deficiente, em especial do folato, é a principal causa de hiper-homocisteinemia nesses casos. Embora ainda não haja consenso sobre a dose exata e a forma de utilização do folato em suplementos e sobre adequação alimentar ou fortificação de cereais para o tratamento da hiper-homocisteinemia, diversos estudos realizados em pacientes com doença vascular periférica mostraram que o folato, isoladamente, pode reduzir as concentrações de homocisteína, bem como a concentração de alguns marcadores biológicos do processo de aterosclerose. No entanto, estudos recentes não comprovaram esse benefício sobre o processo inflamatório associado à hiper-homocisteinemia. Desta forma, embora a utilização isolada do folato seja uma terapêutica custo-efetiva no controle da hiper-homocisteinemia, seu impacto na evolução das doenças arteriais ainda persiste inconclusivo. Esta revisão abordará os efeitos obtidos com as diversas formas de utilização do folato no tratamento da hiper-homocisteinemia.

Concentração de homocisteína em pacientes portadores de doença arterial periférica atendidos em um serviço público de saúde

Contexto: Estudos recentes indicam que a concentração elevada de homocisteína é um fator de risco importante e prevalente para doença vascular aterosclerótica coronariana, cerebral e periférica. Objetivo: Tendo em vista a escassez de informações relacionadas à hiper-homocisteinemia em doença arterial periférica (DAP) no Brasil e as peculiaridades de nossa população, o objetivo deste estudo foi avaliar a frequência de hiper-homocisteinemia em amostra dessa população em um ensaio clínico com indivíduos portadores e não portadores de DAP atendidos em um serviço público brasileiro. Métodos: Foi realizado um estudo ensaio clínico caso-controle com 40 indivíduos portadores de DAP confirmada por Doppler ultrassom (grupo DAP) em comparação com 20 indivíduos voluntários sem DAP (grupo-controle). Resultados: A DAP predominante foi a isquemia crônica de membros (75%). As concentrações plasmáticas medianas de homocisteína de jejum foram significantemente maiores no grupo DAP do que no grupo-controle (16,7 versus 12,9 µmol/L, p = 0,001), tanto nos homens (18,9 versus 14,0 µmol/L, p = 0,005) quanto nas mulheres (13,9 versus 11,2 µmol/L, p = 0,025). Quanto à proporção de indivíduos com hiper-homocisteinemia, observou-se tendência a uma maior frequência no grupo DAP (60%) em relação ao grupo-controle (30%) (p = 0,054). Nos indivíduos com idade inferior a 60 anos foram encontrados valores medianos de homocisteína significantemente mais elevados no grupo DAP (p = 0,041). Conclusões: A hiper-homocisteinemia é um fator de risco importante e foi encontrada em 60% dos indivíduos portadores de DAP atendidos em um serviço público no Brasil.

Dietas vegetarianas e desempenho esportivo

As evidências atuais apontam benefícios da dieta vegetariana para a saúde humana. Contudo, a partir da adoção de práticas vegetarianas mais restritivas, confirmam-se os riscos à saúde. As dietas vegetarianas são caracterizadas pelo elevado consumo de carboidratos, fibras, magnésio, potássio, folato e antioxidantes, podendo apresentar deficiências em aminoácidos e ácidos graxos essenciais, cálcio, zinco, ferro e cobalamina. Pesquisas experimentais em humanos indicam que vegetarianos e não-vegetarianos apresentam capacidade aeróbica semelhante. em relação ao desempenho em atividades de força e potência muscular, as pesquisas são escassas, mas as existentes não apontam diferenças significativas. Situações de risco cardiovascular têm sido confirmadas, devido ao provável quadro de hiperhomocisteinemia, em decorrência da baixa ingestão de cobalamina. As dietas vegetarianas são isentas de creatina, o que resulta em estoques musculares mais baixos nessa população. Possivelmente ocorrem alterações hormonais e metabólicas em resposta às dietas vegetarianas, como baixos níveis de testosterona e androstenediona. A função imune parece não ser prejudicada. Dessa forma, a prática de dietas vegetarianas apresenta-se compatível com a prática esportiva cotidiana, desde que bem planejada para evitar deficiências nutricionais.

Serum homocysteine and physical exercise in patients with Parkinson's disease

Background: Hyperhomocysteinemia is a major risk factor for cerebral and peripheral vascular diseases, as well as cortical and hippocampal injury, including an increased risk of dementia and cognitive impairment. Elevated serum homocysteine (Hcy) concentrations are common in patients with Parkinson's disease (PD) who have been treated with levodopa; however, physical exercises can help reduce Hcy concentrations. The aim of the present study was to compare serum Hcy levels in patients with PD who partook in regular physical exercises, sedentary PD patients, and healthy controls.Methods: Sixty individuals were enrolled in the present study across three groups: (i) 17 patients who did not partake of any type of exercise; (ii) 24 PD patients who exercised regularly; and (iii) 19 healthy individuals who did not exercise regularly. All participants were evaluated by Hoehn and Yahr scale, the Unified Parkinson's Disease Rating Scale (UPDRS) and Schwab and England scale (measure daily functionality). The serum levels of Hcy were analyzed by blood samples collected of each participant. An analysis of variance and a Tukey's post hoc test were applied to compare and to verify differences between groups. Pearson's correlation and stepwise multiple regression analyses were used to consider the association between several variables.Results: Mean plasma Hcy concentrations in individuals who exercised regularly were similar to those in the healthy controls and significantly lower than those in the group that did not exercise at all (P = 0.000). In addition, patients who did not exercise were receiving significantly higher doses of levodopa than those patients who exercised regularly (P = 0.001). A positive relationship between levodopa dose and Hcy concentrations (R(2) = 0.27; P = 0.03) was observed in patients who did not exercise, but not in those patients who exercised regularly (R(2) = 0.023; P = 0.15).Conclusions: The results of the present study suggest that, even with regular levodopa therapy, Hcy concentrations in PD patients who exercise regularly are significantly lower than in patients who do not exercise and are similar Hcy concentrations in healthy controls.

Freqüência da mutação 844ins68 do gene da cistationina beta-sintetase em pacientes com trombose venosa profunda

A hiper-homocisteinemia, resultante da deficiência na conversão da homocisteína em cistationina, constitui em fator de risco isolado para doenças vasculares. A mutação 844ins68 do gene da cistationina beta-sintetase é um fator adicional de risco para a trombose venosa profunda. O objetivo deste estudo foi avaliar a freqüência da mutação 844ins68 do gene da cistationina beta-sintetase em pacientes com trombose venosa profunda. Foram avaliados em estudo caso-controle 95 pacientes com trombose venosa profunda, a presença da mutação 844ins68 no éxon 8 do gene da cistationina beta-sintetase. Como critério de inclusão foi adotada a presença de trombose venosa profunda confirmada pelo dúplex ou flebografia. O grupo controle constituiu-se de 95 doadores de sangue, sem história familiar prévia de trombose venosa, com sexo, grupo étnico e idades pareados aos do grupo de estudo. Foram coletados 5 mL de sangue venoso com o uso de anticoagulante EDTA de cada participante. O DNA foi extraído dos leucócitos pelo método DTAB e CTAB. A detecção da mutação do gene foi realizada por amplificação de um segmento gênico por PCR, com iniciadores que flanqueiam a região de inserção e com revelação em gel de agarose a 2%, corado com brometo de etídio, sob luz UV. O fragmento correspondente ao alelo normal contém 184 pares de base e o correspondente ao alelo mutante, 252 pares de base. O teste exato de Fisher foi utilizado na análise dos resultados. A condição heterozigota para a mutação foi encontrada em 14,73% dos pacientes e em 3,1% dos indivíduos do grupo controle (p = 0,009). A freqüência do alelo mutante mostrou diferença significativa (p = 0,01), sendo 0,074 para os pacientes versus 0,016 para o grupo controle. Não foram encontrados casos de homozigose.

Doença arterial coronariana: Um novo paradigma na AIDS

The HIV-infected individuals have been identified as a peculiar group whose propensity to the development of abnormalities in lipids metabolism supports the hypothesis that AIDS itself can be considered as an independent risk factor for the occlusive diseases development. The AIDS progression, as well as the therapy against HIV has been capable to show an array of metabolic disturbances that HIV-infected patients are prone to. These metabolic alterations affect the fate of plasmatic lipids and homocysteine as a result of three factor mainly: (i) the viral infection per se which triggers the development of hypertriglyceridemia and hipocholesterolemia; (ii) multiple vitamins and micronutrients deficiencies, that favors an onset of hyperhomocysteinemia; (iii) the state-of-the-art therapy for HIV infection, which is accompanied to idiosyncratic effects encompassing the lipid metabolism. In this context, a variety of risk factors to atherosclerosis can be identified in the HIV-infected individual. Of note, it must be considered that once life expectancy of these patients has been expanded due to the effective therapy, on the other hand they can accelerate atherosclerotic disease or its pathological appearance in the same extent.

Risk-assessment algorithm and recommendations for venous thromboembolism prophylaxis in medical patients

The risk for venous thromboembolism (VTE) in medical patients is high, but risk assessment is rarely performed because there is not yet a good method to identify candidates for prophylaxis. Purpose: To perform a systematic review about VTE risk factors (RFs) in hospitalized medical patients and generate recommendations (RECs) for prophylaxis that can be implemented into practice. Data sources: A multidisciplinary group of experts from 12 Brazilian Medical Societies searched MEDLINE, Cochrane, and LILACS. Study selection: Two experts independently classified the evidence for each RF by its scientific quality in a standardized manner. A risk-assessment algorithm was created based on the results of the review. Data synthesis: Several VTE RFs have enough evidence to support RECs for prophylaxis in hospitalized medical patients (eg, increasing age, heart failure, and stroke). Other factors are considered adjuncts of risk (eg, varices, obesity, and infections). According to the algorithm, hospitalized medical patients ≥40 years-old with decreased mobility, and ≥1 RFs should receive chemoprophylaxis with heparin, provided they don't have contraindications. High prophylactic doses of unfractionated heparin or low-molecular-weight-heparin must be administered and maintained for 6-14 days. Conclusions: A multidisciplinary group generated evidence-based RECs and an easy-to-use algorithm to facilitate VTE prophylaxis in medical patients. © 2007 Rocha et al, publisher and licensee Dove Medical Press Ltd.

Associação do padrão de ingestão lípidica com a qualidade da dieta, resistência insulínica e homocisteinemia em adultos

Objectives: To evaluate the association between the consumption of different dietary fats with the quality of the diet, insulin resistance, and hyperhomocysteinemia in adults. Methods: Cross-sectional study conducted with 624 overweight subjects (73.7% females). Assessments of food intake (24h food recall and health eating index-HEI), anthropometry, and biochemical assays of fasting glucose, insulin (HOMA-IR and β calculus) and homocysteinemia were performed. Results: The low quality of diet was associated with the vegetable oil at 3rd quintile (≥1.5-2.0 servings) showed risk 2.9 times and cholesterol at quintiles 2nd, 3rd, and 4th was 2.0 times. HOMA-IR was higher at 5th quintile of saturated fat (≥10,7% - total caloric value) with risk of 60% and hyperhomocysteinemia the vegetable oil at 3rd quintile (>1.5-2.0 servings) with risk of 12.0 times and 5th (≥3.5 servings) 7.1 times. However, significance disappeared when adjusted for anthropometric variables. Conclusion: Dietary fats were associated with the harm diet quality, insulin resistance, and hyperhomocysteinemia. However, associations are dependant of demographic variables, dietetic, and nutritional state. © 2011 CELOM.