MiR -18a -5p aggravates homocysteine -induced myocardial injury via autophagy / 中南大学学报(医学版)

OBJECTIVES@#Hyperhomocysteinaemia (Hcy) is an independent risk factor for cardiovascular and cerebrovascular diseases. MicroRNA (miR)-18a-5p is closely related to cardiovascular diseases. This study aims to investigate the effects of miR-18a-5p on homocysteine (Hcy)-induced myocardial cells injury.@*METHODS@#H9c2 cells were transfected with miR-18a-5p mimic/miR-18a-5p mimic negative control (NC) or combined with Hcy for intervention, and untreated cells were set as a control group. The transfection efficiency was verified by real-time RT-PCR, and cell counting kit-8 (CCK-8) assay was used to determine cell viability. Flow cytometry was used to detect apoptosis and reactive oxygen species (ROS) levels. Western blotting was performed to measure the protein levels of microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, Beclin1, p62, Bax, Bcl-2, and Notch2. Dual luciferase reporter assay was used to detect the interaction of miR-18a-5p with Notch2.@*RESULTS@#Compared with the control, treatment with Hcy or transfection with miR-18a-5p mimic alone, or combined treatment with Hcy and miR-18a-5p mimic/miR-18a-5p mimic NC significantly reduced the H9c2 cell viability, promoted apoptosis and ROS production, up-regulated the expressions of Bax and Beclin, down-regulated the expressions of Bcl-2, p62, and Notch2, and increased the ratio of LC3-II/LC3-I (all P<0.05). Compared with the combined intervention of miR-18a-5p mimic NC and Hcy group, the above indexes were more significantly changed in the combined intervention of miR-18a-5p mimic and Hcy group, and the difference between the 2 groups was statistically significant (all P<0.05). There is a targeted binding between Notch2 and miR-18a-5p.@*CONCLUSIONS@#MiR-18a-5p could induce autophagy and apoptosis via increasing ROS production in cardiomyocytes, and aggravate Hcy-induced myocardial injury. Notch2 is a target of miR-18a-5p.

The specific impact of uremic toxins upon cognitive domains: a review / O impacto específico de toxinas urêmicas em domínios cognitivos: uma revisão

ABSTRACT One of the mechanisms proposed for chronic kidney disease (CKD)-related cognitive impairment is the accumulation of uremic toxins due to the deterioration of the renal clearance function. Cognition can be categorized into five major domains according to its information processing functions: memory, attention, language, visual-spatial, and executive. We performed a review using the terms 'uric acid', 'indoxyl sulfate', 'p-cresyl sulfate', 'homocysteine', 'interleukins' and 'parathyroid hormone'. These are the compounds that were found to be strongly associated with cognitive impairment in CKD in the literature. The 26 selected articles point towards an association between higher levels of uric acid, homocysteine, and interleukin 6 with lower cognitive performance in executive, attentional, and memory domains. We also reviewed the hemodialysis effects on cognition. Hemodialysis seems to contribute to an amelioration of CKD-related encephalopathic dysfunction, although this improvement occurs more in some cognitive domains than in others.

RESUMO Um dos mecanismos propostos para explicar o comprometimento cognitivo relacionado à doença renal crônica (DRC) é o acúmulo de toxinas urêmicas devido à deterioração da função de depuração renal. A cognição pode ser categorizada em cinco domínios principais de acordo com suas funções de processamento de informações: memória, atenção, linguagem, visual-espacial e executiva. Realizamos uma revisão usando os termos "ácido úrico", "indoxil sulfato", "p-cresil sulfato", "homocisteína", "interleucinas" e "paratormônio". Estes são os compostos que se mostraram fortemente associados ao comprometimento cognitivo na DRC na literatura. Os 26 artigos selecionados apontam para uma associação entre níveis mais elevados de ácido úrico, homocisteína e interleucina-6 com menor desempenho cognitivo nos domínios executivo, atenção e de memória. Também revisamos os efeitos da hemodiálise na cognição. A hemodiálise parece contribuir para uma melhoria da disfunção encefalopática relacionada à DRC, embora essa melhora ocorra mais em alguns domínios cognitivos do que em outros.

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.

Betaína e Colina dietéticas relacionadas à homocisteína plasmática: estudo de base populacional, São Paulo, Brasil / Betaine and Choline Intakes are related to total plasma homocysteine: health survey of São Paulo, Brazil

Fundamentos: Elevadas concentrações de homocisteína plasmática (Hcyp) têm sido associadas ao risco aumentado de doenças cardiovasculares. A Hcyp pode ser diminuída por meio da remetilação à metionina, que usa folato ou betaína como doador do grupo metil.Objetivos: Avaliar a ingestão de betaína e colina e sua relação com a homocisteína em residentes do município de São Paulo. Métodos: Obtidos dados de 584 indivíduos, de ambos os sexos, a partir do estudo de base populacional ISA-SP 2008. Médias geométricas de Hcyp foram analisadas de acordo com tercis de ingestão de colina e betaína e foi aplicado teste de tendência.Resultados: Foram analisados 584 indivíduos: 222 (38,0%) homens e 362 (62,0%) mulheres, com média de idade 55,0±19,0 anos. A prevalência de hiper-homocisteinemia foi maior entre os homens (28,0%), idosos (21,0%) e indivíduos com menor renda familiar (21,0%). Cerca de 31,0% dos indivíduos com hiper-homocisteinemia apresentou deficiência de folato (<7,5 nmol/L) e 26,0%, deficiência de vitamina B12 (<200 pmol/L). Observou-se diminuição nas médias geométricas de homocisteína conforme aumento nos tercis de betaína em ambos os sexos,adultos, eutróficos e em todas as categorias de escolaridade. A colina esteve relacionada à Hcyp em ambos os sexos, indivíduos de maior renda familiar, não fumantes e consumidores de bebidas alcoólicas. Conclusões: Este estudo sugere a importância da ingestão de betaína por sua associação inversa com a concentração de Hcyp em adultos e idosos do município de São Paulo. A colina desempenhou papel protetor em subgrupos específicos da população.

Background: High concentrations of plasma homocysteine (Hcyp) have been associated with increased risk of cardiovascular diseases. Hcyp can be decreased by remethylation to methionine, which uses folate or betaine as a donor of the methyl group. Objectives: To evaluate the intake of betaine and choline and its relation to homocysteine in residents of the city of São Paulo. Methods: Data from 584 individual, of both sexes, from the population-based study ISA-SP 2008. Geometric averages of Hcyp were analyzed according to choline and betaine intake tertiles and trend test was applied. Results: The study analyzed 584 individuals: 222 (38.0%) men and 362 (62.0%) women, mean age 55.0 ± 19.0 years. The prevalence of hyperhomocysteinemia was higher among men (28.0%), the elderly (21.0%) and those with lower household income (21.0%). Approximately 31.0% of individual with hyperhomocysteinemia presented folate deficiency (<7.5 nmol/L) and 26.0% presented vitamin B12 deficiency (<200 pmol/L). There was a decrease in the geometric means of homocysteine according to an increase in betaine tertiles in both sexes, adults, normal and in all categories of education. Choline was related to Hcyp in both sexes, higherhousehold income individuals, non-smokers and alcohol consumers. Conclusions: This study suggests the importance of betaine intake due to its inverse relationship with the concentration of Hcyp in adults and elderly in the city of São Paulo. Choline played a protective role in specific subgroups of the population.

Hiperhomocisteinemia/homocisteinuria como factor de riesgo cardiovascular en niños y adolescentes / Hyperhomocysteinemia/homocystinuria as cardiovascular risk factor children and adolescents

Actualmente, las enfermedades cardiovasculares son la primera causa de muerte a nivel mundial. Aunque, este tipo depatologías afectan en mayor proporción a adultos mayores, su proceso inicia desde la infancia. Hoy por hoy la hiperhomocisteinemia/homocisteinuria se ha considerado un factor de riesgo cardiovascular independiente y tan importante o másque otros clásicos. Existen cada vez más evidencias que resulta necesario identificar a tiempo esta alteración y procedera su tratamiento preventivo. Algunas de las causas para padecer esta patología en edad temprana son; la insuficienteingestión de ácido fólico, vitamina B6 o vitamina B12, las cuales son un conjunto de vitaminas importantes que funcionancomo cofactores de la 5-10-metilentetrahidrofolato reductasa (MTHFR), cistationina β sintetasa (CBS) y metionina adenosiltransferasa(MAT); tres enzimas principales del metabolismo de la homocisteína. Sin embargo, aún no se conoce en sutotalidad las consecuencias del incremento de homocisteína en niños y jóvenes.

Currently, cardiovascular disease is the leading cause of death worldwide. Although, this type of disease affects a greaterproportion to older adults, the process starts since childhood. Today, hyperhomocysteinemia has been considered anindependent cardiovascular risk factor, as important or more than other classic factors. There is increasing evidence thattime is necessary to identify the disorder and provide treatment for prevention. Some of the reasons for developingthis disease at an early age: the insufficient intake of folic acid, vitamin B6 and vitamin B12, which are a set of importantvitamins that act as cofactors 5-10-methylenetetrahydrofolate reductase (MTHFR), cystathionine β synthase (CBS) andmethionine adenosyltransferase (MAT), three major enzymes of homocysteine metabolism. However, still not fully knownconsequences of homocysteine increase in children and youth.

Level of homocysteine in patients with peripheral arterial disease treated at a public health care facility

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 por cento). 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 por cento) em relação ao grupo-controle (30 por cento) (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 por cento dos indivíduos portadores de DAP atendidos em um serviço público no Brasil.

Background: Recent studies have suggested that high level of homocysteine is an important and prevalent risk factor for coronary, cerebral and peripheral arterial disease. Objective: In light of the lack of information on hyperhomocysteinemia in peripheral arterial disease (PAD) in Brazil and the peculiarities of its population, the objective of the present study was to evaluate the frequency of hyperhomocysteinemia in a sample of the Brazilian population by means of a clinical trial involving individuals with and without PAD being treated at a public health care facility. Methods: A case-controlled clinical trial was conducted with 40 individuals with a PAD diagnosis confirmed by Doppler ultrasound (PAD group) compared with 20 volunteer individuals without PAD (control group). Results: The predominant PAD was chronic limb ischemia (75 percent). Median fasting plasma levels of homocysteine were significantly higher in the PAD group than in the control group (16.7 vs. 12.9 ìmol/L, p = 0.001), both in men (18.9 vs. 14.0 ìmol/L, p = 0.005) and women (13.9 vs. 11.2 ìmol/L, p = 0.025). As to the proportion of individuals with hyperhomocysteinemia, a tendency toward a higher frequency was observed in the PAD group (60 percent) in relation to the control group (30 percent) (p = 0.054). Individuals aged less than 60 years had significantly high median values of homocysteine in the PAD group (p = 0.041). Conclusions: Hyperhomocysteinemia was a prevalent and important risk factor in individuals with PAD treated at a public health care facility in Brazil.

Homocysteine in cardiovascular disease: a culprit or an innocent bystander?

Whether hyperhomocysteinemia is a cardiovascular risk factor or is just an epiphenomenon is a subject of debate. More than 20 prospective and 30 retrospective studies on the topic have been published. Despite huge literature available, an unequivocal view has not been firmly established. Medical fraternity is still witnessing differing opinions regarding need to treat hyperhomocysteinemia. A medical practitioner needs to be well informed of developments and current opinion on this subject as it has a strong bearing on a major emerging public health problem of cardiovascular disease (CVD). This review presents the two views - for and against the acceptance of association between hyperhomocysteinemia and cardiovascular disease - and their basis. The two views are examined in the light of clinical, epidemiologic and genetic studies, reviews and meta-analyses available. Following conclusion was drawn from the exercise: The available evidence indicates that homocysteine is not an innocent bystander; it is an independent risk factor for CVD. The need for homocysteine-lowering therapy is however not yet unequivocally established. Physicians need to be vigilant of the updates on this much-debated topic thrusted on them time and again.

Homocisteina: nuevo factor de riesgo cardiovascular / Homocysteine: new factor cardiovascular risk

La gran cantidad de evidencia acumulada sobre el papel de la homocisteína como factor de riesgo cardiovascular es cada día más fuerte. Una concentración de homocisteína plasmática elevada induce cambios patológicos en la pared arterial asociándose a un incremento en el riesgo de desarrollar aterosclerosis, la cual se manifiesta comúnmente como accidentes cerebrovasculares, cardiovasculares y vasculares periféricos. Diferentes estudios realizados han sido dirigidos a determinar si la disminución de los niveles de homocisteína plasmáticos pueden ser de utilidad para prevenir eventos oclusivos. En la actualidad la realización de exámenes de laboratorio para cuantificar los niveles de homocisteína pueden ser considerados en pacientes con ateroesclerosis prematuras con una historia familiar de arteroesclerosis, donde la hiperhomocisteinemia es un factor de riesgo común en estos pacientes. El tratamiento de la hiperhomocisteinemia es simple y con riesgo terapéutico mínimo. Este desorden es usualmente corregido con suplementos vitamínicos que contienen ácido fólico.

Comparison of serum homocysteine level in metformin versus glibenclamide treated type 2 DM patients

Diabetes mellitus is the most common cause of renal failure, blindness, non- traumatic amputation and neuropathy. Homocysteine, a sulfurated amino acid, has a close correlation with Methionine and Cysteine. The conversion of Methionine to Homocysteine and Cysteine is required coenzymes like vitamin B6, B12 and Folate. The effect of Metformin on serum Homocysteine level by decreasing vitamin B12 level in patients with type 2 diabetes mellitus was described previously. This is a prospective clinical trail study among patients with type 2 diabetes mellitus in Shiraz. 76 patients were divided into two groups [38 patients in each group]. First group treated with Metformin 500-2000 mg/day and the second group treated with Glibenclamide 5-20 mg/day with follow up period of at least 6 months. Hb and MCV were used in follow up to detect megaloblastic anemia, indicator of B12 and folate deficiency. Fasting plasma Homocysteine level Hb A1C and blood sugar were measured in baseline and at 3 and 6 months follow up periods. There was no significant difference between age, sex, weight, height and BMI and baseline serum profile between the two groups. Homocysteine level increased significantly in Metformin group at 3 and 6 months[P=0.003 and 0.001 respectively]. Mean plasma homocysteine level after 6 months were 10.98 +/- 0.58 micro mol/l in Metformin and 10.0 +/- 0.88 micro mol/l in Glibenclamide group, with significant difference between the two groups [P=0.001]. Metformin increases the plasma Homocysteine level. Metformin will accumulate highly in gastrointestinal wall and cause malabsorption of vitamin B12, therefore we can conclude that the use of Metformin for 6 months can cause vitamin B12 malabsorption and increase in plasma homocysteine level. Increase in plasma homocysteine level was 7.54% in our study that is higher in comparing to the other studies. It can be explained by longer duration of Metformin therapy in our study. Rising in Homocysteine levels may have detrimental effect on vessels that need further study

Effect of folic acid supplementation on plasma homocysteine levels in patients with coronary artery disease

Our objective was to asses the effect of folic acid supplementation on homocysteine levels in patients with established coronary artery disease. This quasi experimental study was carried out at department of Cardiology, KRL Hospital, Islamabad during the period of May 2002 to December 2003. The patients with raised fasting homocysteine levels were supplemented with 5mg of folic acid and were followed up for a period of six months. The primary end point was the change in homocysteine level and secondary end point was untoward cardiac events. In primary end point, folic acid supplementations decreased mean plasma homocysteine concentration in 17 [56.7%] of the patients with mean change in homocysteine concentration of up to 7.7 +/- 9.3 micro mol/l. There was evidence of substantial interindividual variation in the homocysteine response including an increase in homocysteine in 13 [43.3%] subjects [mean increase 5.5 +/- 10.7 pmol/l]. In secondary end point, three patients were admitted with exacerbation of chronic stable angina; they were ruled out for any myocardial damage. Twenty seven patients had uneventful follow up. The variability of response to folic acid replacement with paradoxical rise in homocysteine levels in certain individuals mandate that we retest the homocysteine level in patients undergoing folic acid replacement to establish its continued salutary response

O consumo de café e sua relação com a hiperhomocisteinemia: revisão / Coffee intake and the relation with hyperhomocisteinemia: a review

Coffee is one of the most worldwide consumed beverages, and Brazil is its major source. Coffee plants belong to the Rubiacea e family, and there are many species, although only C. arabica and C. canephora (Robusta) have commercial value. The chemical composition of green coffee depends on the species, climatic conditions, processing and storage. Recently, coffee intake has been related to increased plasma homocysteine levels ­ this non-proteica minoacid is one of the risk factors for occlusive cardiovascular diseases,one of the main causes of death in industrialized countries. This finding points out to the relevance of analysis of coffee constituents involved inincreased homocysteine plasma levels. Caffeine, chlorogenic acid and diterpenes (caffestol and caveol) are important substances present in coffee,which exert physiological effects

El café es una de las bebidas mas consumidas en el mundo, siendo Brasil el mayor produto rmundial. El café pertenece a la família Rubiáceas, y existen numerosas especies, pero solamente la C. arabica y la C. canéfora (Robusta) tienen valor comercial. La composición química del café verde depende dela especie, condiciones climáticas, de procesamiento y de almacenamiento. Recientemente, el consumo de café ha sido relacionado al aumento de los niveles de homocisteína plasmática ­ este aminoácido no proteico es uno de los factores de riesgo para las enfermedades cardiovasculares oclusivas, las cuales responden por las principales causas de muerte en países industrializados ­ esto es relevante para la investigación que busca los componentes del café, responsables por el aumento de los niveles de homocisteínaplasmática. La cafeína, el acido clorogénico, diterpenos (cafestol y cahweol) son importantes substancias presentes en el café que ejercen efectos fisiológicos en el organismo

A bebida de café é uma das bebidas mais consumidas no mundo, sendo o Brasil o seu maior produtor. As plantas de café pertencem à família Rubiaceae, e possuem inúmeras espécies, mas somente a C. arábica e C. canéfora (Robusta) têm valor comercial. A composição química do café verde depende da espécie, condições climáticas, processamento e estocagem. Recentemente, o consumo de café tem sido relacionado ao aumento dos níveis de homocisteína plasmática - esse aminoácido não protéico é um dos fatores de risco para a ocorrência de doenças cardiovasculares oclusivas, uma das principais causas de morte em países industrializados - tal fato torna relevante a investigação sobre os componentes do café, envolvidos no incremento dos níveis de homocisteína plasmática. A cafeína, o ácido clorogênico e os diterpenos (cafestol e caveol) são importantes substâncias presentes no café, exercendo efeitos fisiológicos no organismo

Hiper-homocisteinemia causando aterogênese na aorta de coelhos: modelo experimental / Hyperhomocysteinemia causing atherogenesis in rabbits´aorta: an experimental model

Objetivo: Este estudo tem por objetivo avaliar os efeitos da homocisteinemia plasmática elevada na formação da placa aterosclerótica na aorta de coelhos. Material e método: Realizou-se estudo experimental comparativo em dois grupos homogêneos de coelhos durante 60 dias. Foram utilizados 20 coelhos da linhagem New Zealand divididos em dois grupos de 10 animais: grupo controle (C) e grupo metionina (M). Todos os animais receberam a mesma dieta sólida e 500 ml de água. Os animais do grupo M receberam 2 ml de uma solução de metionina na concentração de 200 mg/ml a cada 24 horas. Foram colhidas amostras de sangue para a dosagem de colesterol, triglicerídeos, HDL, LDL e homocisteína após 0, 30 e 60 dias. Os animais foram submetidos a eutanásia por dose letal de anestésico no 60° dia. A aorta torácica e a aorta abdominal foram retiradas para estudo anatomopatológico...

Homocyst(e)ine and atherosclerosis: recent advances

Los resultados de numerosos estudios que incluyen más de 10.000 pacientes, sugieren que los niveles elevados de homocisteína en plasma (>10 µM) constituyen un factor de riesgo para la arteriosclerosis. Asimismo, diferentes análisis han demostrado la asociación de niveles elevados de homocisteína en plasma con enfermedad [vascular periférica], infarto de miocardio, enfermedad coronaria y enfermedad cerebrovascular, siendo además un factor predictivo de accidente cerebrovascular o de mortalidad. Estudios más recientes sugieren que el ácido fólico sería la piedra angular en el tratamiento de los niveles elevados de homocisteína. Aunque en 1990 se sugirió que la hiperhomocisteinemia era un factor de riesgo fácilmente reversible para aterosclerosis oclusiva, fueron necesarios numerosos ensayos clínicos para determinar si la disminución de la homocisteína afectaría la evolución de la enfermedad aterosclerótica; sin embargo los resultados de los ensayos clínicos en curso no estarán disponibles por muchos años.

Homocysteine and vascular disease.

For more than 20 years, moderately raised concentrations of total homocysteine have been associated with an increased risk of atherothrombotic vascular events but only recently has evidence mounted to suggest that the association may be causal. The association is independent of other factors, it is fairly consistent across many studies, it is strong and dose-related, and it is biologically plausible. However, the evidence needs to be strengthened by a systematic review of all comparable studies and the demonstration, in randomised trials, that lowering total homocysteine is followed by a significant reduction in atherothrombotic vascular disease. In addition, the measurement of total homocysteine needs to be standardised. If these can be achieved then total homocysteine measurement will become another useful marker of vascular risk, multivitamin therapy will be another therapeutic option for people at risk of atherothrombotic vascular disease, and fortification of food with folic acid will rise high on the political and public health agenda.

Homocyst(e)ine and risk of cardiovascular disease in the multiple risk factor intervention trial.

A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for upto 20 years, were analysed for homocyst(e)ine. Cases involved non-fatal myocardial infractions, identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease, monitored through 1990. The non-fatal myocardial infarction occurred within 7 years of sample collection, whereas the majority of coronary heart disease deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: myocardial infarction cases, 12.6 micromol/L; myocardial infarction controls, 13.1 micromol/L; coronary heart disease death cases, 12.8 micromol/L; and coronary heart disease controls, 12.7 micromol/L. Odds ratios versus quartile 1 for coronary heart disease deaths and myocardial infarctions combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase (C-reactive) protein. These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.