Research progress on the role and mechanism of endothelial dysfunction in hyperhomocysteine-induced atherosclerosis / 生理学报

Hyperhomocysteinemia (HHcy) is considered to be an independent risk factor for cardiovascular diseases, but the molecular mechanisms underlying its pathogenesis are not fully understood. Endothelial dysfunction is a key initiating factor in the pathogenesis of atherosclerosis, which is commonly observed in almost all HHcy-induced vascular diseases. HHcy promotes oxidative stress, inhibits nitric oxide production, suppresses hydrogen sulfide signaling pathway, promotes endothelial mesenchymal transition, activates coagulation pathways, and promotes protein N-homocysteination and cellular hypomethylation, all of which can cause endothelial dysfunction. This article reviews the specific links between HHcy and endothelial dysfunction, and highlights recent evidence that endothelial mesenchymal transition contributes to HHcy-induced vascular damage, with a hope to provide new ideas for the clinical treatment of HHcy-related vascular diseases.

Association between maternal plasma one-carbon biomarkers during pregnancy and fetal growth in twin pregnancies / 中华妇产科杂志

Objective: To characterize the relationship between the levels of plasma methyl donor and related metabolites (including choline, betaine, methionine, dimethylglycine and homocysteine) and fetal growth in twin pregnancies. Methods: A hospital-based cohort study was used to collect clinical data of 92 pregnant women with twin pregnancies and their fetuses who were admitted to Peking University Third Hospital from March 2017 to January 2018. Fasting blood was collected from the pregnant women with twin pregnancies (median gestational age: 18.9 weeks). The levels of methyl donors and related metabolites in plasma were quantitatively analyzed by high-performance liquid chromatography combined with mass spectrometry. The generalized estimation equation was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and neonatal outcomes of twins, and the generalized additive mixed model was used to analyze the relationship between maternal plasma methyl donors and related metabolites levels and fetal growth ultrasound indicators. Results: (1) General clinical data: of the 92 women with twin pregnancies, 66 cases (72%) were dichorionic diamniotic (DCDA) twin pregnancies, and 26 cases (28%) were monochorionic diamniotic (MCDA) twin pregnancies. The comparison of the levels of five plasma methyl donors and related metabolites in twin pregnancies with different basic characteristics showed that the median levels of plasma choline and betaine in pregnant women ≥35 years old were higher than those in pregnant women <35 years old, and the differences were statistically significant (all P<0.05). (2) Correlation between plasma methyl donor and related metabolites levels and neonatal growth indicators: after adjusting for confounding factors, plasma homocysteine level in pregnant women with twins was significantly negatively correlated with neonatal birth weight (β=-47.9, 95%CI:-94.3- -1.6; P=0.043). Elevated methionine level was significantly associated with decreased risks of small for gestational age infants (SGA; OR=0.5, 95%CI: 0.3-0.9; P=0.021) and low birth weight infants (OR=0.6, 95%CI: 0.4-0.9; P=0.020). Increased homocysteine level was associated with increased risks of SGA (OR=1.5, 95%CI: 1.0-2.2; P=0.029) and inconsistent growth in twin fetuses (OR=1.9, 95%CI: 1.0-3.7; P=0.049). (3) Correlation between the levels of plasma methyl donors and related metabolites and intrauterine growth indicators of twins pregnancies: for every 1 standard deviation increase in plasma choline level in pregnant women with twin pregnancies, fetal head circumference, abdominal circumference, femoral length and estimated fetal weight in the second trimester increased by 1.9 mm, 2.6 mm, 0.5 mm and 20.1 g, respectively, and biparietal diameter, abdominal circumference and estimated fetal weight increased by 0.7 mm, 3.0 mm and 38.4 g in the third trimester, respectively, and the differences were statistically significant (all P<0.05). (4) Relationship between plasma methyl donor and related metabolites levels in pregnant women with different chorionicity and neonatal birth weight and length: the negative correlation between plasma homocysteine level and neonatal birth weight was mainly found in DCDA twin pregnancy (β=-65.9, 95%CI:-110.6- -21.1; P=0.004). The levels of choline, betaine and dimethylglycine in plasma of MCDA twin pregnancy were significantly correlated with the birth weight and length of newborns (all P<0.05). Conclusion: Homocysteine level is associated with low birth weight in twins, methionine is associated with decreased risk of SGA, and choline is associated with fetal growth in the second and third trimesters of pregnancy.

Effect of / 生物医学与环境科学（英文）

Objective@#This study aimed to investigate the effects of @*Methods@#In this study, 0.1% DMG was supplemented in 20% casein diets that were either folate-sufficient (20C) or folate-deficient (20CFD). Blood and liver of rats were subjected to assays of Hcy and its metabolites. Hcy and its related metabolite concentrations were determined using a liquid chromatographic system.@*Results@#Folate deprivation significantly increased pHcy concentration in rats fed 20C diet (from 14.19 ± 0.39 μmol/L to 28.49 ± 0.50 μmol/L; @*Conclusion@#DMG supplementation exhibited hypohomocysteinemic effects under folate-sufficient conditions. By contrast, the combination of folate deficiency and DMG supplementation has deleterious effect on pHcy concentration.

CBS promoter hypermethylation increases the risk of hypertension and stroke

OBJECTIVES: Cystathionine β-synthase is a major enzyme in the metabolism of plasma homocysteine. Hyperhomocysteinemia is positively associated with hypertension and stroke. The present study was performed to examine the possible effects of Cystathionine β-synthase promoter methylation on the development of hypertension and stroke. METHODS: Using quantitative methylation-specific PCR, we determined the Cystathionine β-synthase methylation levels in 218 healthy individuals and 132 and 243 age- and gender-matched stroke and hypertensive patients, respectively. The relative changes in Cystathionine β-synthase promoter methylation were analyzed using the 2-ΔΔCt method. The percent of the methylated reference of Cystathionine β-synthase was used to represent the Cystathionine β-synthase promoter methylation levels. RESULTS: In this study, the Cystathionine β-synthase promoter methylation levels of hypertensive and stroke participants were both higher than that of the healthy individuals (median percentages of the methylated reference were 50.61%, 38.05% and 30.53%, respectively, all p<0.001). Multivariable analysis showed that Cystathionine β-synthase promoter hypermethylation increased the risk of hypertension [odds ratio, OR (95% confidence interval, CI)=1.035 (1.025-1.045)] and stroke [OR (95% CI)=1.015 (1.003-1.028)]. The area under the curve of Cystathionine β-synthase promoter methylation was 0.844 (95% CI: 0.796-0.892) in male patients with hypertension and 0.722 (95% CI: 0.653-0.799) in male patients with stroke. CONCLUSION: Cystathionine β-synthase promoter hypermethylation increases the risk of hypertension and stroke, especially in male patients.

Folic acid and diseases - supplement it or not? / Ácido fólico e doenças - suplementá-lo ou não?

SUMMARY Introduction: folic acid is a water soluble vitamin, which is synthetically-produced and found in fortified foods and supplements. Folate is found naturally in plants, such as the dark green leafy vegetables. Folate is not synthesizedde novo by humans, therefore the daily requirements are met from the dietary intake of folic acid supplements or food rich in this vitamin. Folate deficiency could lead to numerous common health problems. Hyperhomocysteinemia and the possibility of malignancy developments are the long term consequences of this deficit albeit contradictory findings on these claims. Methods: the articles included in this review focused on recent updated evidence-based reports and meta-analyses on the associations of the serum folate/folic acid and the various diseases found globally. Results: the benefit of folic acid supplementation in the pre-conception period for the prevention of neural tube defects (NTDs) was well established and it was suggested that counseling sessions should be given to women with previous pregnancies affected by NTDs. However, supplementation of folic acid and its medicinal effects in the treatment of other diseases were contradictory and unclear. Conclusion: more detailed investigations into the health benefits of folic acid are needed before it could be recommended for supplementation, treatment or prevention of some of the diseases discussed in this review.

RESUMO Introdução: ácido fólico é uma vitamina solúvel em água produzida sinteticamente e encontrada em alimentos e suplementos enriquecidos. O folato é encontrado naturalmente em plantas, como vegetais folhosos verde-escuros. O folato não é sintetizado de novo por seres humanos; portanto, as necessidades diárias são satisfeitas a partir da ingestão de suplementos de ácido fólico ou alimentos ricos nessa vitamina. A deficiência de folato pode levar a inúmeros problemas de saúde comuns. Hiper-homocisteinemia e a possibilidade de desenvolver malignidades são as consequências a longo prazo desse déficit, ainda que os resultados sejam contraditórios sobre essas afirmações. Métodos: os artigos incluídos nesta revisão tratam de relatórios recentes atualizados com base em provas e metanálises sobre a associação entre o folato/ácido fólico e várias doenças encontradas globalmente. Resultados: o benefício da suplementação de ácido fólico no período de pré-concepção para a prevenção de defeitos do tubo neural (DTN) foi bem estabelecido e foi sugerido que sessões de aconselhamento devem ser providas às mulheres com gravidezes anteriores afetadas por DTN. No entanto, os benefícios da suplementação de ácido fólico e os efeitos medicinais no tratamento de outras doenças são contraditórios e pouco claros. Conclusão: investigações mais detalhadas sobre os benefícios do ácido fólico são necessárias antes que a suplementação seja recomendada para tratamento ou prevenção de algumas das doenças discutidas nesta revisão.

Metabolismo da homocisteína em doenças neurológicas / Homocysteine metabolism in neurologic disorders

OBJETIVO: Realizar uma revisão sobre o metabolismo do aminoácido sulfurado homocisteína, analisando como elevações de seus níveis séricos se correlacionam com a fisiopatologia das mais diversas doenças neurológicas, assim como sobre o tratamento da hiper-homocisteinemia. MÉTODO: Revisão não sistemática de artigos que abordassem o papel da homocisteína associado a doenças neurológicas.Foi priorizada a utilização de artigos que apresentassem no título as palavras-chave "homocisteína" ou "hiper-homocisteinemia",associadas a palavras-chave contendo as enfermidades neurológicas de maior prevalência como acidente vascular cerebral, doença de Alzheimer, doença de Parkinson e outras. Foram utilizadas as bases de dados do PubMed, Lilacs e Google Scholar. RESULTADOS: Foram utilizados 35 artigos em inglês e 2 artigos em português para a confecção desta revisão. CONCLUSÃO: A homocisteína se encontra elevada em associação com as mais diversas doenças neurológicas. Contudo, em muitas delas não está estabelecido se esse aumento é um achado secundário ou se representa um papel da homocisteína na patogênese dessas enfermidades. Mais estudos são necessários para estabelecer o papel da homocisteína em situações neurológicas.O tratamento da hiper-homocisteinemia é fácil, sendo feito com reposição de vitamina B12 e, principalmente, de folatos.

OBJECTIVE: Review the metabolism of sulfur amino acid homocysteineand how elevation of its serum levels is correlated with the pathophysiologyof several neurological diseases, as well as the treatment of hyperhomocysteinemia. METHOD: A non-systematic review of articles discussing the role of homocysteine associated with neurological diseases was performed. The use of articles that presented in the title the keywords "homocysteine" or "hyperhomocysteinemia" associated with keywords containing the most prevalent neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease and others were preferred. The search was underdone through PubMed, Google Scholar and Lilacs databases. RESULTS: There were selected 35 articles in English and 2 articles in Portuguese in this this review. CONCLUSION: High levels of homocysteine are associated with various neurological disorders. However, in many of these are not established whether this increase is a consequence of these disorders or if homocysteine plays a role in the pathogenesis of these diseases. More studies are needed to establish the participation ofhomocysteine in neurological disorders. The treatment of hyperhomocysteinemia is easy, being done with replacement of vitamin B12and especially folate.

Metabolism and gene polymorphisms of the folate pathway in Brazilian women with history of recurrent abortion / Metabolismo e polimorfismos gênicos da via do folato em mulheres brasileiras com história de aborto recorrente

PURPOSE: To investigate the association between polymorphisms in genes that encode enzymes involved in folate- and vitamin B12-dependent homocysteine metabolism and recurrent spontaneous abortion (RSA). METHODS: We investigated the C677T and A1298C polymorphisms of the methylenetetrahydrofalate reductase gene (MTHFR), the A2756G polymorphism of the methionine synthase gene (MS) and the 844ins68 insertion of the cystathionine beta synthetase gene (CBS). The PCR technique followed by RFLP was used to assess the polymorphisms; the serum levels of homocysteine, vitamin B12 and folate were investigated by chemiluminescence. The EPI Info Software version 6.04 was used for statistical analysis. Parametric variables were compared by Student's t-test and nonparametric variables by the Wilcoxon rank sum test. RESULTS: The frequencies of gene polymorphisms in 89 women with a history of idiopathic recurrent miscarriage and 150 controls were 19.1 and 19.6% for the C677T, insertion, 20.8 and 26% for the A1298C insertion, 14.2 and 21.9% for the A2756G insertion, and 16.4 and 18% for the 844ins68 insertion, respectively. There were no significant differences between case and control groups in any of the gene polymorphisms investigated. However, the frequency of the 844ins68 insertion in the CBS gene was higher among women with a history of loss during the third trimester of pregnancy (p=0.003). Serum homocysteine, vitamin B12 and folate levels id not differ between the polymorphisms studied in the case and control groups. However, linear regression analysis showed a dependence of serum folate levels on the maintenance of tHcy levels. CONCLUSION: The investigated gene polymorphisms and serum homocysteine, vitamin B12 and folate levels were not associated with idiopathic recurrent miscarriage in the present study. Further investigations are needed in order to confirm the role of the CBS 844ins68 insertion in recurrent miscarriage. .

OBJETIVO: Investigar a associação entre polimorfismos nos genes que codificam enzimas envolvidas no metabolismo da homocisteína dependente de folato e vitamina B12 e aborto espontâneo recorrente. MÉTODOS: Investigamos os polimorfismos C677T e A1298C no gene methilenotetrahidrofalato redutase (MTHFR); o polimorfismo A2756G no gene metionina sintase (MS) e a inserção 844ins68 no gene da cistationina beta-sintetase (CBS). A técnica de PCR seguido por RFLP foi utilizada para investigar os polimorfismos. Os níveis séricos de homocisteína, vitamina B12 e de folato foram investigados pela técnica de quimioluminescência. O Software Epi Info versão 6.04 foi utilizado para realizar a análise estatística. As variáveis paramétricas foram comparadas pelo teste t de Student e as variáveis não paramétricas pelo teste de Wilcoxon rank sum. RESULTADOS: As frequências dos polimorfismos gênicos em 89 mulheres com história de aborto recorrente idiopático e 150 controles foram de 19,1 e 19,6% para o C677T; 20,8 e 26% para o A1298C; 14,2 e 21,9% para o A2756G e 16,4 e 18% para a inserção 844ins68, respectivamente. Não houve diferenças significantes entre os grupos caso e controle em todos os polimorfismos dos genes investigados. No entanto, a frequência da inserção 844ins68 no gene CBS foi maior entre mulher com histórico de perdas no terceiro trimestre da gravidez p=0.003). Os níveis de homocisteína, vitamina B12 e folato séricos não foram diferentes entre os polimorfismos estudados nos grupos casos e controles. No entanto, a análise de regressão linear mostrou dependência dos níveis séricos de folato na manutenção dos níveis de homocisteína. CONCLUSÃO: Os polimorfismos gênicos investigados, assim como homocisteína, vitamina B12 e os níveis séricos de folato não foram associados com abortos recorrentes idiopático no presente estudo. Novas investigações devem ser realizados a fim de confirmar o papel da inserção 844ins68-CBS nos abortos recorrentes. .

Consumo dietético, variantes genéticas e relação com níveis sanguíneos de folato, ácido fólico não metabolizado e homocisteína após a fortificação mandatória de ácido fólico: estudo de base populacional - ISA - Capital / Dietary intake and genetic variants of folate and its relation to folate, unmetabolized folic acid and homocysteine blood concentrations after mandoty folic acid fortification population based study ISA-Capital

Em diversos países, inclusive no Brasil, a fortificação de alimentos com ácido fólico (AF) foi adotada como política pública de prevenção e combate à deficiência nutricional da vitamina, motivados principalmente pela redução da incidência dos defeitos do tubo neural. No período pós-fortificação observa-se tanto a evolução positiva do consumo e nível sérico da vitamina quanto a diminuição da concentração plasmática de homocisteína, e ainda, o aumento do ácido fólico não metabolizado na maioria desses países. Não se conhece ainda os efeitos biológicos do AFNM, no entanto, considera-se que o AFNM pode ser um fator relevante nas questões de segurança associadas com alto consumo de AF. Objetivo: Avaliar o consumo dietético e nível de folato, homocisteína e ácido fólico não metabolizado após a fortificação mandatória de alimentos com ácido fólico, e a interação com os polimorfismos envolvidos no metabolismo do folato e homocisteína. Metodologia: Os dados foram oriundos do estudo transversal de base populacional ISA Capital 2008 conduzido em uma amostra representativa de residentes do município de São Paulo, de ambos os sexos, e com idade acima de 14 anos. Coletou-se recordatórios alimentares de 24 horas e amostra de sangue em jejum de 12 horas para análises bioquímicas e moleculares. As análises estatísticas foram realizadas no programa STATA®, versão 13.0, com nível de significância de 5 por cento . Resultados: O estudo foi conduzido em 750 indivíduos, sendo 53,1 por cento mulheres e média de idade 40,7 (IC95 por cento 38,8-42,5) anos. A média de consumo e nível de folato foi de 375,8 (IC95 por cento 363,0-388,6) mcg/dia e 13 (IC95 por cento 12,0-13,9) ng/ml, respectivamente...

Food fortification is an important strategy in public health policy for controlling micronutrient malnutrition, and a major contributory factor in the eradication of micronutrients deficiencies. Motivated by the reduction in the occurrence of neural tube defects, countries worldwide, including Brazil, adopted food fortification with folic acid (FA). Folic acid fortification has increased dietary intakes of folic acid and folate status, but it is also associated with the presence of circulating FA. Although the metabolism and biological effects of circulating of folic acid are not well known, it may be a contributing factor in safety concerns associated with high oral doses of folic acid. Objective: To assess the folate intake and status, homocysteine and circulating FA after mandatory fortification with folic acid, and interaction with polymorphisms involved in 1-carbon metabolism. Material and Methods: Data were from 750 individuals aged > 14 years old who participated of a cross-sectional population-based survey in Sao Paulo City-Brazil. Fasting blood samples and information about food intake based on two measures of 24 hour food recall were collected. All analyses were carried out using STATA (version 13.0) and p-value <.05 was considered to be statistically significant in all tests. Results: Results were from 750 individuals...

Alterações metabólicas e inflamatórias em condições de estresse oxidativo / Metabolic and inflammatory changes in oxidativestress situations

O estresse oxidativo pode ser definido com o desequilíbrio entre os níveis de compostos pró-oxidantes e antioxidantes, com predomínio dos primeiros. O estado pró-oxidante vem sendo relacionado a várias patologias, como doença cardiovascular, doenças neurodegenerativas, doenças auto-imunes e cânceres, ora como sua causa, em alguns casos como consequência. Assim, torna-se importante determinar quais alterações metabólicas e inflamatórias estão relacionadas com o estresse oxidativo, para auxiliar no diagnóstico e prognóstico dessas doenças. Além dos fatores de risco clássicos, esta revisão chama a atenção para possíveis novos biomarcadores relacionados ao estresse oxidativo, entre estes estão a mieloperoxidase, paraoxonase, homocisteína e determinação do estado antioxidante.

Oxidative stress can be defined as an imbalance between the levels of pro-oxidant and antioxidant compounds, with the former predominating. The pro-oxidant status has been linked to several diseases, such as cardiovascular, neurodegenerative and autoimmune diseases and cancers, at times as the cause, at others as a result. Thus, it is highly relevant to determine which metabolic and inflammatory disorders are associated with oxidative stress, to help in the diagnosis and prognosis of these diseases. In addition to the classical risk factors, this review highlights possible new biomarkers related to oxidative stress, among which are myeloperoxidase, paraoxonase, homocysteine and determination of the antioxidant status.

Endothelial Dysfunction and Increased Carotid Intima-Media Thickness in the Patients with Slow Coronary Flow

Flow mediated brachial dilatation (FMD) and carotid intima-media thickness (IMT) have been a surrogate for early atherosclerosis. Slow coronary flow in a normal coronary angiogram is not a rare condition, but its pathogenesis remains unclear. A total of 85 patients with angina were evaluated of their brachial artery FMD, carotid IMT and conventional coronary angiography. Coronary flow was quantified using the corrected thrombosis in myocardial infarction (TIMI) frame count method. Group I was a control with normal coronary angiography (n = 41, 56.1 +/- 8.0 yr) and group II was no significant coronary stenosis with slow flow (n = 44, 56.3 +/- 10.0 yr). Diabetes was rare but dyslipidemia and family history were frequent in group II. Heart rate was higher in group II than in group I. White blood cells, especially monocytes and homocysteine were higher in group II. The FMD was significantly lower in group II than in group I. Elevated heart rate, dyslipidemia and low FMD were independently related with slow coronary flow in regression analysis. Therefore, endothelial dysfunction may be an earlier vascular phenomenon than increased carotid IMT in the patients with slow coronary flow.

Impacto do exercício físico nos níveis de homocisteína, um fator de risco para aterosclerose: revisão sistemática / Impact of exercise on homocysteine levels, a risk factor for atherosclerosis: systematic review

O objetivo dessa revisão sistemática foi identificar na literatura, estudos que avaliaram os efeitos de um programa regular de exercício físico na concentração plasmática de homocisteína. Foi realizada uma busca eletrônica nas seguintes bases de dados: Medline, Ovid, PubMed, Science Direct, Scopus, Sport Discus, Web of Science, Lilacs e Scielo. Utilizou-se como descritores os termos "homocisteína" combinado com "exercício físico", sendo que este,pode ser substituído por qualquer um dos termos a seguir: "atividade física", "aptidão cardiorrespiratória", "treinamento", "aptidão" ou "redução de peso". Os respectivos termos foram traduzidos para o Inglês. Foram identificados 42 artigos no processo inicial de busca. A análise prévia foi realizada por meio da leitura dos resumos. Dos 42 artigos identificados, 35 foram descartados por não respeitarem os critérios de inclusão. Selecionou-se assim, sete estudos, os quais foram obtidos na íntegra e, após a leitura dos mesmos, todos foram inclu-ídos na amostra final do presente artigo de revisão. Verificou-se que quatro, dos sete artigos analisados, demonstraram que houve redução significativa na concentração de homocisteína naqueles indivíduos submetidos a um programa regular de exercício físico, quando comparados aos seus controles sedentários. Assim, sugere-se que indivíduos que praticam exercício físico regularmente, parecem ter seus níveis de homocisteína significativamente reduzidos, podendo contribuir na prevenção e/ou tratamento das doenças cardiovasculares. Contudo, esses achados devem ser interpretados com cautela, devido as limitações apresentadas por essa revisão sistemática.

The aim of this systematic review was to identify in the literature, studies that assessed the effects of a regular exercise program on plasma homocysteine concentration. An electronic search was performed in the following databases: Medline, Ovid, PubMed, Science Direct, Scopus, Sport Discus, Web of Science, Lilacs and Scielo. The terms used as descriptors were "homocysteine" combined with "exercise", whereas the last one could be replaced by any of the following terms: "physical activity", "cardiorespiratory fitness", "training", "fitness" or "weight reduction". The respective terms were translated from Portuguese. We identified 42 articles in the initial search. The previous analysis was done by reading the abstracts. From the 42 articles identified, 35 were excluded for not respect the inclusion criteria. Finally, after reading of the full text, seven studies were selected and included in this review sample. Four of them demonstrated a significant reduction in homocysteine concentration in individuals who were submitted to a regular exercise program, when compared with their sedentary controls. Thus, it is suggested that individuals who exercise regularly seem to have their homocysteine levels significantly reduced, which may contribute to the prevention or treatment of cardiovascular diseases. However, these findings should be interpreted with caution, because the limitations of this systematic review.

Hiper-homocisteinemia como fator de risco cardiovascular / Hyperhomocysteinemia as a cardiovascular risk factor

Introdução: A hiper-homocisteinemia tem sido apontada como fator de risco para doença vascular periférica. Objetivo: Realizar uma revisão de literatura sobre a homocisteína como fator de risco para doenças cardiovasculares. Método: Foi realizada uma pesquisa bibliográfica descritiva nas bases de dados SciELO e PubMed. Resultados: Incluíram-se 22 artigos na revisão de literatura. Alguns estudos têm demonstrado associação entre a hiper-homocisteinemia e risco cardiovascular, colocando-a como um importante fator de risco para doenças vasculares da atualidade. Contudo, não foram encontrados estudos conclusivos que a demonstrassem como um fator de risco cardiovascular independente. Para alguns autores ela pode ser decorrente de um evento vascular prévio e não um fator de risco. Conclusão: Embora diversos estudos mostrem associação entre a hiper-homocisteinemia e risco cardiovascular, pesquisas adicionais são necessárias para esclarecer se tal alteração é causa ou consequência de doenças cardiovasculares, bem como elucidar os mecanismos pró-ateroscleróticos relacionados com a hiper-homocisteinemia.

Introduction: Hyperhomocysteinemia has been identified as a risk factor for peripheral vascular disease. Objective: The main objective was doing a review of literature on homocysteine as a risk factor for cardiovascular disease. Methods: It was performed a descriptive bibliographic research in the electronic libraries SciELO and PubMed. Results: In this review twenty two scientific articles were included. Some studies showed an association between hyperhomocysteinemia and cardiovascular risk, placing the former as an important risk factor for vascular disease today. However, there are no conclusive studies demonstrating the hyperhomocysteinemia as an independent predictor of cardiovascular risk, for some authors it may be a consequence of a previous vascular event and not a risk factor. Conclusion: Although several studies have shown an association between hyperhomocysteinemia and cardiovascular risk, additional studies are needed to clarify whether the hyperhomocysteinemia is a cause or consequence of cardiovascular disease, and elucidate the pro-atherosclerotic mechanisms associated with hyperhomocysteinemia.

Asociación de variantes funcionales en genes del metabolismo de la homocisteína con riesgo de trombosis venosa profunda e hiperhomocisteinemia en individuos del Sur de Chile / Association of functional variants in homocysteine metabolism genes, deep venous thrombosis risk and hyperhomocysteinemia in Southern Chilean subjects

Introducción: La Trombosis Venosa Profunda (TVP) es un importante problema de salud en la sociedad moderna. Evidencia reciente sugiere una asociación entre variantes funcionales en genes del metabolismo de la homocisteína con TVP. Sin embargo, los resultados entre poblaciones son contradictorios. En este trabajo, evaluamos la potencial asociación entre la presencia de polimorfismos en genes del metabolismo de la homocis-teína y susceptibilidad a TVP e hiperhomocisteinemia en sujetos chilenos. Métodos: Un total de 231 individuos, 77 pacientes con diagnóstico de TVP y 154 controles fueron incluidos en el estudio. Polimorfismos en los genes Metilenotetrahi-drofolato reductasa (MTHFR) y Cistationina p-sintetasa fueron genotipificados por PCR-RFLP Las concentraciones de homocisteína basal fueron cuantificadas mediante Inmunoensayo de Fluorescencia Polarizada. Resultados: La distribución genotípica y frecuencias alélicas del polimorfismo MTHFR C677T fue significativamente diferente entre pacientes y controles (p<0.01). Odds Ratio para TVP asociada al genotipo homocigoto fue 3.68 (I.C. 95 por ciento: 1.628-8.337, p<0.01). Por el contrario, la distribución genotípica de la variante CBS 844ins68 fue similar en ambos grupos (OR=1.82, I.C. 95 por ciento: 0.636-5.234, p=0.257). Además, los portadores del genotipo homocigoto MTHFR 677TT presentaron niveles más elevados de homocisteína plasmática. Conclusiones: El polimorfismo MTHFR C677T constituye un biomarcador de riesgo de TVP en población chilena, y se relaciona a mayores niveles de homo-cisteína en sujetos homocigotos. Los resultados sugieren que la detección molecular de esta variante debería ser incluida en el estudio básico de Trombofilia en nuestra población.

Background: Deep Venous Thrombosis (DVT) is an important health problem in modern society. Recent evidence suggests an association between functional variants in homocysteine metabolism genes and DVT. However, findings in different populations have been contradictory. In this work, we evaluated the potential association between the presence of polymorphisms in homocysteine metabolism genes, DVT susceptibility and hyperhomocysteinemia in Chilean subjects. Methods: A total of 231 individuals, 77 patients with diagnosis of DVT and 154 controls were included in this study. Common variants in Metylenete-trahydrofolate reductase (MTHFR) and Cistationine p-synthetase (CBS) genes were genotyped by PCR-RFLP. Basal homocysteine was quantified by Fluorescence Polarization Immunoassay. Results: Genotype distribution and allelic frequencies of MTHFR C677T polymorphism were significantly different between patients and controls. Odds Ratio for DVT associated to homozygous status was 3.68 (95 percent C.I., 1.628-8.337, p<0.01). On the other hand, the genotype distribution of the CBS 844ins68 variant was similar in both groups (OR 1.82, 95 percent C.I.: 0.636-5.234, p=0.257). In addition, the individuals carrying the MTHFR 677TT homozygous genotype exhibited higher levels of homocysteine. Conclusion: The MTHFR C677T polymorphism constituted a molecular biomarker of DVT in Chilean population, and related to higher levels of homocysteine in homozygote subjects. The results suggest that the molecular detection of this polymorphism should be included in the basic screening for thrombophilia in our population.

Cardiac biomarkers in the diagnosis, prognosis and management of coronary artery disease: A primer for internists.

Initially coined in 1989, biomarkers have become a cornerstone of modern cardiovascular medicine. The past decade has borne witness to the rapid transition of cardiac biomarkers from bench to bedside in the management of patients with coronary artery disease. The implementation of cardiac biomarkers has transformed the internists' approach to cardiovascular patients. This article reviews several cardiac biomarkers in the context of diagnosis, prognosis, risk-assessment and management of patients at risk of adverse cardiovascular outcomes. Biomarkers are presented according to their relevant role in the atherosclerotic cascade, a pathologic classification of particular value for internists, as it defines the role of these agents in the pathogenesis of heart disease. Where pertinent, limitations of cardiac biomarkers are discussed, thus allowing the discerning practitioner to remain cognizant of situations that may lead to spurious marker elevation or suppression. The review concludes with highlights on novel avenues of biomarker research that promise an exciting future for these entities.

Genetics of homocysteine metabolism and associated disorders

Homocysteine is a sulfur-containing amino acid derived from the metabolism of methionine, an essential amino acid, and is metabolized by one of two pathways: remethylation or transsulfuration. Abnormalities of these pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is observed in approximately 5 percent of the general population and is associated with an increased risk for many disorders, including vascular and neurodegenerative diseases, autoimmune disorders, birth defects, diabetes, renal disease, osteoporosis, neuropsychiatric disorders, and cancer. We review here the correlation between homocysteine metabolism and the disorders described above with genetic variants on genes coding for enzymes of homocysteine metabolism relevant to clinical practice, especially common variants of the MTHFR gene, 677C>T and 1298A>C. We also discuss the management of hyperhomocysteinemia with folic acid supplementation and fortification of folic acid and the impact of a decrease in the prevalence of congenital anomalies and a decline in the incidence of stroke mortality.

Association of Methylenetetrahydrofolate Reductase (MTHFR 677C>T and 1298A>C) Polymorphisms and Haplotypes with Silent Brain Infarction and Homocysteine Levels in a Korean Population

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) is the main regulatory enzyme for homocysteine metabolism. In the present study, we evaluated whether the MTHFR 677C>T and 1298A>C gene polymorphisms are associated with SBI and plasma homocysteine concentration in a Korean population. MATERIALS AND METHODS: We enrolled 264 patients with SBI and 234 healthy controls in South Korea. Fasting plasma total homocysteine (tHcy) concentrations were measured, and genotype analysis of the MTHFR gene was carried out. RESULTS: The plasma tHcy levels were significantly higher in patients with SBI than in healthy controls. Despite a significant association between the MTHFR 677TT genotype and hyperhomocysteinemia, the MTHFR 677C>T genotypes did not appear to influence susceptibility to SBI. However, odds ratios of the 1298AC and 1298AC + CC genotypes for the 1298AA genotype were significantly different between SBI patients and normal controls. The frequencies of 677C-1298A and 677C-1298C haplotypes were significantly higher in the SBI group than in the control group. CONCLUSION: This study demonstrates that the MTHFR 1298A>C polymorphism is a risk factor for SBI in a Korean population. The genotypes of 677C>T and 1298A>C polymorphisms interact additively, and increase the risk of SBI in Korean subjects.

Effect of methionine load on homocysteine levels, lipid peroxidation and DNA damage in rats receiving ethanol / Efeito da carga de metionina nos níveis de homocisteína, peroxidação lipídica e dano ao DNA em ratos que receberam etanol

Changes in the metabolism of methionine can cause hyperhomocysteinemia, inducing a triad of atherosclerosis, hypertension, and increased oxidative stress. The generation of free radicals and oxidative damage to DNA is important in the liver damage caused by ethanol. In this study, the effect of methionine overload associated or otherwise with acute administration of ethanol on homocysteine values, damage to DNA, lipoperoxidation and vitamin E was evaluated. Thirty rats were divided into 3 groups: Group Ethanol 24 hours (EG24), Group Methionine 24 hours (MG24), and Group Methionine and Ethanol 24 hours (MEG24). TBARS, vitamin E, GS and, homocysteine values were determined and the Comet assay was carried out. Increased GSH, vitamin E and homocysteine levels were observed for MEG24, and increased TBARS were observed in EG24. The Comet assay showed an increase in DNA damage in EG24 and DNA protection in MEG24. The administration of ethanol decreased antioxidant levels and increased TBARS, indicating the occurrence of oxidative stress with possible DNA damage. The combination of methionine and ethanol had a protective effect against the ethanol-induced damage, but increased the levels of homocysteine.

Alterações no metabolismo da metionina podem ocasionar hiper-homocisteinemia, quadro indutivo de aterosclerose, hipertensão e aumento do estresse oxidativo. A geração de radicais livres e dano oxidativo ao DNA são importantes na injúria hepática provocada pelo etanol. Neste estudo avaliaram-se os efeitos da sobrecarga de metionina associada ou não à administração aguda de etanol sobre valores de homocisteína, dano ao DNA, lipoperoxidação e vitamina E. Foram utilizados 30 ratos Wistar distribuídos em 3 Grupos: Grupo Etanol 24 horas (GE24), Grupo Metionina 24 horas (GM24) e Grupo Metionina e Etanol 24 horas (GME24). Realizaram-se determinações hepáticas de SRATB, vitamina E, GSH, homocisteína e Teste do Cometa e determinações plasmáticas de GSH e homocisteína. Valores aumentados de GSH, vitamina E e homocisteína foram observados para o GME24, e de SRATB no GE24. O Teste do Cometa mostrou aumento do dano ao DNA no GE24 e proteção ao DNA no GME24. A administração de etanol diminuiu os níveis de antioxidantes e aumentou o de SRATB, indicando ocorrência de estresse oxidativo, podendo ocasionar dano ao DNA. A presença da metionina associada com o etanol agiu como protetora contra os danos do etanol, mas aumentou os níveis de homocisteína.

Homocysteine, Hydrogen sulfide (H2S) and NMDA-Receptor in Heart Failure.

Mitochondrial mechanism of oxidative stress and matrix metalloproteinase (MMP) activation was unclear. Our recent data suggested that MMPs are localized to mitochondria and activated by peroxynitrite, which causes cardiovascular remodeling and failure. Recently, we have demonstrated that elevated levels of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy) increase oxidative stress in the mitochondria. Although HHcy causes heart failure, interestingly, it is becoming very clear that Hcy can generate hydrogen sulfide (H2S), if the enzymes cystathionine β-synthase (CBS) and cystathionine -lyase (CGL) are present. H2S is a strong anti-oxidant and vasorelaxing agent. Paradoxically, it is interesting that Hcy, a precursor of H2S can be cardioprotective. The CGL is ubiquitous, while the CBS is not present in the vascular tissues. Therefore, under normal condition, only half of Hcy can be converted to H2S. However, there is strong potential for gene therapy of CBS to vascular tissue that can mitigate the detrimental effects of Hcy by converting it to H2S. This scenario is possible, if the activities of both the enzymes (CBS and CGL) are increased in tissues by gene therapy.

Serum biochemical markers in rheumatoid arthritis.

Rheumatoid arthritis (RA) characterized by local and systemic effects of inflammation has a wide range of biochemical markers implicated directly or indirectly to its pathogenesis. In the present study, homocysteine, cortisol, adenosine deaminase (ADA), ferritin, malondialdehyde (MDA) and -tocopherol in serum of RA patients and healthy individuals were estimated to assess if they contribute to the disease process. The markers of disease activity such as erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were also measured. The study group included a total of 45 subjects, including 30 RA patients and the rest being healthy individuals. RA group showed a significant increase in the levels of homocysteine, ADA and MDA, and a significant decrease in α-tocopherol compared to the healthy individuals. However, cortisol and ferritin levels did not show any significant change. Also, there was no significant correlation between the studied serum markers and markers of disease activity. Our results indicate that these biochemical markers contribute independently to the pathogenesis of RA.

Serum homocysteine in indian adolescents.

Objective. To assay serum homocysteine levels and examine its association with conventional risk factors for cardiovascular disease (CVD) in Indian adolescents. Methods. This was a cross-sectional study conducted in tertiary care hospital in northern India in apparently healthy adolescents aged 10 – 19 yr. A pre-designed questionnaire was used to assess conventional risk factors. Serum homocysteine levels of ≥ 12μmol/L, serum triglycerides ≥ 150 mg% and serum cholesterol ≥ 200 mg% were taken as hyperhomocysteinemia, hypertriglyceridemia and hypercholesterolemia, respectively. Serum high-density lipoprotein (HDL) ≥ 40 mg% was considered protective for CVD. Results. In 103 subjects, 36.87 % females, mean serum homocysteine level was 11.649 ±0.416μmol/L. Hyperhomocysteinemia was present in 46 (44.6%, 95% CI: 34.965-54.75) subjects. Dietary deficiency of vitamin B12 and folic acid, body mass index (BMI) > 84th percentile and altered lipid profile were associated with hyperhomocysteinemia on univariate analysis. After multivariate adjustment for BMI and vegetarian diet, low serum HDL (OR: 23.81, 95% CI: 2.86-200; p =0.003) and serum hypertriglyceridemia (OR: 4.17, 95% CI: 1.51 – 13.51; p = 0.022) had independent association with hyperhomocysteinemia. Conclusion. Since we have also found an association between hyperhomocysteinemia and low serum HDL levels and hypertriglyceridemia, which are conventional risk factors for CVD, interventional strategies are urgently needed among adolescents for prevention of CVD.