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.

Exploration of the risk factors of essential hypertension with hyperhomocysteinemia: A hospital-based study and nomogram analysis

OBJECTIVES: To explore the risk factors of essential hypertension with hyperhomocysteinemia (H-type hypertension) and design a nomogram to predict this risk. METHODS: A hospital-based study was conducted on 1,712 individuals, including 282 patients with H-type hypertension, 105 patients with simple hypertension, 645 individuals with hyperhomocysteinemia, and 680 healthy controls. Logistic regression and nomogram models were applied to evaluate the risk factors. RESULTS: Logistic regression showed that advanced age, male sex, high body mass index (BMI), high total cholesterol levels, high glucose levels, and high creatinine levels were risk factors of H-type hypertension in the healthy population and were integrated into the nomogram model. Advanced age, male sex, high BMI, high total cholesterol levels, and high glucose levels were shown to be risk factors of H-type hypertension in the hyperhomocysteinemia population. Male sex and high creatinine levels were shown to be risk factors of H-type hypertension in the hypertension population. Nomogram analysis showed that the total factor score ranged from 106 to 206, and the corresponding risk rate ranged from 0.05 to 0.95. CONCLUSIONS: Men are more likely to have H-type hypertension, and advanced age, high BMI, high total cholesterol levels, and high glucose levels are risk factors of H-type hypertension in healthy and hyperhomocysteinemia populations. Furthermore, high creatinine level is a risk factor of H-type hypertension in healthy and hypertension populations. Nomogram models may be used to intuitively evaluate H-type hypertension risk and provide a basis for personalized interventions.

Human tissue kallikrein-1 protects against the development of erectile dysfunction in a rat model of hyperhomocysteinemia / 亚洲男科学杂志(英文版)

The aim of this study was to investigate the mechanism by which a diet inducing high hyperhomocysteinemia (HHcy) leads to the deterioration of erectile function in rats and whether this is inhibited by expression of the human tissue kallikrein-1 (hKLK1) gene. We established a rat model of HHcy by feeding methionine (Met)-rich diets to male Sprague-Dawley (SD) rats. Male wild-type SD rats (WTRs) and transgenic rats harboring the hKLK1 gene (TGRs) were fed a normal diet until 10 weeks of age. Then, 30 WTRs were randomly divided into three groups as follows: the control (n = 10) group, the low-dose (4% Met, n = 10) group, and the high-dose (7% Met, n = 10) group. Another 10 age-matched TGRs were fed the high-dose diet and designated as the TGR+7% Met group. After 30 days, in all four groups, erectile function was measured and penile tissues were harvested to determine oxidative stress, endothelial cell content, and penis fibrosis. Compared with the 7% Met group, the TGR+7% Met group showed diminished HHcy-induced erectile dysfunction (ED), indicating the improvement caused by hKLK1. Regarding corpus cavernosum endothelial cells, hKLK1 preserved endothelial cell-cell junctions and endothelial cell content, and activated protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) signaling. Fibrosis assessment indicated that hKLK1 preserved normal penis structure by inhibiting apoptosis in the corpus cavernosum smooth muscle cells. Taken together, these findings showed that oxidative stress, impaired corpus cavernosum endothelial cells, and severe penis fibrosis were involved in the induction of ED by HHcy in rats, whereas hKLK1 preserved erectile function by inhibiting these pathophysiological changes.

Níveis plasmáticos de homocisteína em mulheres idosas com úlceras nos pés / Plasma levels of homocystein in women elderly with ulcers in the foot

Introdução: A homocisteína é um amino ácido produzido no fígado e seus níveis elevados apresentam relação com aterosclerose e úlceras. Objetivo: Avaliar os níveis plasmáticos de homocisteína de mulheres idosas com úlceras nos membros inferiores. Métodos: Participaram 40 mulheres idosas, idade média 67,4±6,49 anos, divididas em grupo com úlcera (GU) e controle (GC). A avaliação da presença de úlcera foi realizada por observação, a avaliação da concentração de homocisteína (µmol/L) foi realizada por high performance liquid chromatography (HPLC) e a aferição da pressão arterial foi realizada pelo uso de um esfigmomanômetro aneroide ­ HICO HM 1001. Resultados: Níveis de homocisteína mais elevados para o grupo úlcera 17,69 ± 6,82 versus controle 11,70 ± 1,51. As pressões arteriais sistólica e diastólica não apresentaram diferenças entre os grupos ulcera 134,16±19,28/74,16±11,64 e controle 136,15±16,09/77,69 ± 5,99 respectivamente. Conclusão: Conclui-se que os níveis plasmáticos de homocisteína em mulheres idosas com úlcera estão aumentados.

Introduction: Homocysteine is an amino acid produced in the liver and its elevated levels are related to atherosclerosis and ulcer. Objective: To evaluate the plasma levels of homocysteine of elderly women with ulcers in the lower limbs. Methods: Participated 40 elderly women, mean age 67.4 ± 6.49 years, separated into ulcer (GU) and control (CG) groups. The evaluation of the presence of ulcer was performed by observation, the homocysteine concentration (µmol/L) was evaluated by high performance liquid chromatography (HPLC) and blood pressure was measured using an aneroid sphygmomanometer HICO HM 1001. Results: Higher homocysteine levels for the ulcer group 17.69 ± 6.82 vs control 11.70 ± 1.51. The systolic and diastolic blood pressures did not differences between the ulcer group 134,16±19,28/74,16±11,64 and control group 136,15±16,09/77,69±5,99, respectively. Conclusion: It is concluded that plasma levels of homocysteine in elderly women with ulcer are increased.

Reacciones de N-homocisteinilación asociadas a hiperhomocisteinemia / N-homocysteinylation reactions related to hyperhomocysteinemia / Reações de N-homocisteinilação associadas a hiper-homocisteinemia

Numerosas evidencias clínicas avalan la asociación entre concentración plasmática elevada de homocisteína (hiperhomocisteinemia) y las enfermedades vasculares oclusivas, tales como la aterosclerosis y la trombosis. La homocisteína reducida (Hcy) y su éster cíclico homocisteína-tiolactona (HTL) serían los principales responsables de los efectos nocivos asociados a la hiperhomocisteinemia. Tanto la Hcy como la HTL pueden interactuar espontáneamente con proteínas, a través de reacciones de S y N-homocisteinilación, respectivamente. Ambos procesos provocan alteraciones proteicas post-traduccionales, e inducen cambios estructurales y funcionales a nivel molecular. En los últimos años ha cobrado interés el conocimiento acerca de la HTL y las consecuencias de concentraciones elevadas de este metabolito sobre la salud humana. En las reacciones de N-homocisteinilación, el grupo carbonilo de la HTL se une al grupo ε-amino de los residuos lisina de las proteínas, con lo que se generan grupos sulfhidrilo libres, susceptibles de participar en reacciones redox. Las proteínas N-homocisteiniladas pueden sufrir plegamiento incorrecto de la molécula y daño oxidativo, y en consecuencia se inducen efectos citotóxicos e inmunogénicos. Se ha establecido que la conversión metabólica de la Hcy en HTL y la N-homocisteinilación de proteínas es uno de los mecanismos involucrados en el desarrollo de patologías asociadas con la hiperhomocisteinemia, tales como las enfermedades cardiovasculares y neurodegenerativas.

Increased plasma homocysteine levels (hyperhomocysteinemia) are associated with occlusive vascular diseases, such as atherosclerosis and thrombosis. Reduced homocysteine (Hcy) and its cyclic ester, homocysteine thiolactone (HTL) would be involved in the detrimental effects associated to hyperhomocysteinemia. These two species, Hcy and HTL can spontaneously react with proteins, through S and N-homocysteinylation process, respectively. Both reactions produce post-translational protein changes, impairing structural and functional features. In recent years, interest has been developed in HTL and its effects on human health. N-homocysteinylation is the reaction between the carboxyl group of HTL and ε-amino group of lysine residues, rendering free sulfhydryl groups able to participate in redox reactions. N-homocysteinylated proteins are prone to misfolding and oxidative damage, inducing cytotoxic and immunogenic effects. Metabolic conversion of Hcy to HTL as well as protein N-homocysteinylation is one of the mechanisms underlying the development of pathologies associated to hyperhomocysteinemia, such as cardiovascular and neurodegenerative diseases.

Numerosas evidências clínicas garantem a associação entre concentração plasmática elevada de homocisteína (hiper-homocisteinemia) e as doenças vasculares oclusivas, tais como a aterosclerose e a trombose. A homocisteína reduzida (Hcy) e seu éster cíclico homocisteína tiolactona (HTL) seriam os principais responsáveis pelos efeitos nocivos associados à hiper-homocisteinemia. Tanto a Hcy quanto a HTL podem interagir espontaneamente com proteínas, através de reações de S e N-homocisteinilação, respectivamente. Ambos os processos provocam alterações proteicas pós-traducionais, induzindo alterações estruturais e funcionais em nível molecular. Nos últimos anos, cobrou interesse o conhecimento acerca da HTL e as consequências de concentrações elevadas deste metabólito sobre a saúde humana. Nas reações de N-homocisteinilação, o grupo carbonila da HTL se une ao grupo ε-amino dos resíduos lisina das proteínas, gerando grupos sulfidrila livres, suscetíveis de participar em reações redox. As proteínas N-homocisteiniladas podem sofrer dobramento incorreto da molécula e dano oxidativo, induzindo efeitos citotóxicos e imunogênicos. Estabeleceu-se que a conversão metabólica da Hcy em HTL e a N-homocisteinilação de proteínas é um dos mecanismos envolvidos no desenvolvimento de patologias associadas com a hiper-homocisteinemia, tais como as doenças cardiovasculares e neurodegenerativas.

Associação entre a homocisteína e os polimorfismos do gene da MTHFR em mulheres brasileiras obesas / Association between homocysteine and polymorphisms in MTHFR in Brazilian obese women

Fundamentos: Pesquisas nacionais brasileiras indicam aumento da obesidade e doenças cardiovasculares em mulheres. Objetivo: Determinar a frequência dos polimorfismos 677C>T e 1298A>C do gene da metilenotetra-hidrofolato redutase (MTHFR) em mulheres brasileiras obesas e avaliar sua associação com as concentrações séricas de homocisteína (Hcy),folato e cobalamina, no período após a fortificação das farinhas de trigo e milho com ácido fólico no Brasil. Métodos: Estudo transversal realizado no período de 2008 a 2009, com 133 mulheres obesas. Kits comerciais foramutilizados para realizar análises laboratoriais, incluindo mensuração de lipídeos e glicose por métodos enzimáticos; Hcy total e o folato plasmático, utilizando um imunoensaio competitivo; e cobalamina baseado em quimiluminescência. A genotipagem foi realizada por PCR, seguido por fragmento de restrição enzimática. Resultados: A média de idade dos participantes foi 39,0±4,4 anos e o índice de massa corporal, 32,5±2,1 kg/m². Distribuições dos genótipos encontradas: CC (47%), CT (44%) e TT (9%) para a posição 677 da MTHFR e AA (60%), AC (35%), e CC (5%) para a posição 1298. As concentrações de Hcy correlacionaram-se negativamente com a concentração de folato plasmático no grupo exibindo os genótipos 677CT, 1298AC ou 1298CC (r=0,554, p<0,01). Conclusão: Mulheres brasileiras obesas com genótipos 677TT estudadas apresentaram maiores concentrações de Hcy do que aquelas que apresentaram os genótipos 677CT e 677CC. Além disso, genótipos 1298CC mostraram associação com concentrações de Hcy maiores do que os genótipos 1298AC e 1298AA.

Background: Brazilian national surveys have indicated a rise in obesity and cardiovascular disease in women.Objective: To determine the frequency of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in obese Brazilian women and to assess the potential association of these polymorphisms with serum concentrations of homocysteine (Hcy), folate and cobalamin after fortification of wheat and corn flour with folic acid in Brazil. Methods: A cross-sectional study was conducted from 2008 to 2009 with 133 obese women. Commercial kits were employed to perform laboratory analyses including measurement of lipids and glucose using enzymatic methods, total Hcy and serum folate using a competitive immunoassay and cobalamin based on chemiluminescence. Genotyping was performed by PCR, followed by restriction fragment lengthpolymorphism analysis. Results: The average age of participants was 39.0±4.4 years and mean body mass index was 32.5±2.1kg/m². The distributions of the genotypeswere CC (47%), CT (44%), and TT (9%) for the position MTHFR 677 and AA (60%), AC (35%), and CC (5%) for the position 1298. Hcy levels correlated negatively with serum folate in the group displaying the 677CT, 1298AC, or 1298CC genotypes (r=-0.554, p<0.01). Conclusion: Our findings suggest that obese Brazilian women with genotypes 677TT have higher Hcy concentrations than those carrying the genotypes 677CT and 677CC. Additionally, genotypes 1298CC are associated with higher Hcy concentrations than genotypes 1298AC and 1298AA.

Comparison of homocysteinemia and MTHFR 677CT polymorphism with Framingham Coronary Heart Risk Score / Comparación de homocisteinemia y polimorfismo 677CT MTHFR con el Escore Framingham de Riesgo Coronario

Objective: The Framingham Coronary Heart Disease Risk Score is an important clinical tool. The aim of this cross-sectional study was to compare plasma homocysteine levels and polymorphism 677CT MTHFR with this score to determine the utility of these new biomarkers in clinical practice. Methods: Plasma homocysteine levels determined by chemiluminescence and polymorphism 677CT MTHFR, detected by PCR-RFLP, were compared with Framingham coronary risk score in a cross-sectional survey on 68 men and 165 women. Results: Coronary heart disease risk augmented with an increase in the quartile of plasma homocysteine. In the 2nd, 3rd and 4th quartile of plasma homocysteine, men showed significantly (P < 0.001) higher risk than women. For the highest quartile of plasma homocysteine, OR of high-risk (10-year risk ≥ 20%) compared with the lowest quartile was 17.45 (95% CI: 5.79-52.01). Frequencies of CT and TT genotype and T allele were not over-represented in the individuals with score ≥ 10%. The higher plasma homocysteine concentrations in individuals with score ≥ 10% with respect to those with low risk (P < 0.005 and P < 0.001) were not due to the presence of T allele. The T allele (CT + TT genotypes) of the MTHFR C677T polymorphism was not significantly associated with an increased risk of coronary disease (OR = 1.09, 95% CI = 0.50-2.39, P = 0.844). Conclusions: The present study demonstrated an association between plasma homocysteine levels and the severity of coronary heart disease estimated with the Framingham coronary risk score, and this association appeared to be independent on the genotype of MTHFR. We postulate that plasma homocysteine is effective enough, considered even in isolation.

Objetivo: La puntuación del riesgo coronario de Framingham es una importante herramienta clínica. El objetivo del presente estudio transversal fue comparar los niveles plasmáticos de homocisteína plasmática y el polimorfismo 677CT de la MTHFR con esta herramienta para determinar la utilidad de estos nuevos biomarcadores en la práctica clínica. Métodos: Los niveles de homocisteína plasmática determinados por quimioluminiscencia y el polimorfismo 677CT MTHFR por PCR-RFLP fueron comparados con la puntuación del riesgo coronario de Framingham en un estudio transversal sobre 68 hombres y 165 mujeres. Resultados: El riesgo de enfermedad coronaria aumentó con el incremento en los cuartiles de homocisteína plasmática. En el segundo, tercero y cuarto cuartil de homocisteína plasmática los hombres mostraron significativamente (p < 0.001) mayor riesgo que las mujeres. Para el cuartil más alto de homocisteína plasmática, la OR de riesgo alto (riesgo a 10 años ≥ 20%) comparado con el cuartil más bajo fue 17,45 (IC 95%: 5,79-52,01; p < 0.001). Las frecuencias de los genotipos CT y TT y del alelo T no estuvieron aumentados en los individuos con una puntuación ≥ 10%. Las mayores concentraciones de homocisteína plasmática en los individuos con una puntuación ≥ 10% respecto a los de bajo riesgo (p < 0.005 y p < 0.001) no se debieron a la presencia del alelo T. El alelo T (genotipos CT + TT) del polimorfismo MTHFR C677T no estuvo significativamente asociado con mayor riesgo de enfermedad coronaria (OR = 1.09, IC 95% = 0.50-2.39, p = 0.844). Conclusiones: El presente estudio mostró una asociación entre los niveles de homocisteína plasmática y la severidad de la enfermedad coronaria estimada con el algoritmo de puntuación de riesgo coronario de Framingham y esta asociación resultó ser independiente del genotipo de MTHFR. Postulamos que la homocisteína plasmática es lo suficientemente eficaz, estudiada incluso aisladamente.

Síndrome de Marfan con disección aórtica asociada a tromboembolismo venoso e hiperhomocisteinemia / Marfan syndrome associated with aortic dissection, venous thromboembolism and hyperhomocysteinemia

El síndrome de Marfan es un desorden genético infrecuente, cuyas manifestaciones clínicas afectan a los sistemas cardiovascular, ocular y músculo esquelético, la gravedad de las manifestaciones cardiovasculares son generalmente responsables de la mortalidad de estos pacientes. La enfermedad tromboembólica venosa está íntimamente relacionada con diversos factores de riesgo, congénitos, adquiridos, mixtos o desconocidos. La hiperhomocisteinemia es un factor de riesgo moderado para tromboembolismo venoso. Presentamos el caso de una mujer de 47 años de edad con síndrome de Marfan asociado a disección aórtica tipo A indolora, que simultáneamente padeció trombosis venosa de miembros inferior y superior izquierdos con embolia de pulmón. Al realizar el cribado de trombofilia se constató hiperhomocisteinemia. Con la terapéutica instituida evolucionó favorablemente.

Marfan syndrome is an infrequent genetic disorder of connective tissue whose clinical manifestations mainly affect the cardiovascular, ocular and musculoskeletal systems. Serious cardiovascular manifestations are generally the cause of mortality of Marfan patients. Thromboembolic venous disease is intimately related to different risk factors: inherited, acquired, mixed or unknown; hyperhomocysteinemia is a moderate risk factor for venous thromboembolism. We present the case of a 47-year-old woman with Marfan syndrome associated to a painless type A aortic dissection, who simultaneously suffered venous thromboembolism of left upper and lower limbs with pulmonary embolism. Hyperhomocysteinemia was found through thrombofilia screening. The patient's condition has evolved favorably.

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.

Factores genéticos del sistema hemostático en pacientes jóvenes con infarto agudo del miocardio / Genetic factors of the hemostatic system in young patients with myocardial infarction

La enfermedad arterial coronaria (EAC) es la primera causa de muerte en todo el mundo y representa un problema de salud pública en México. El infarto agudo del miocardio (IAM) representa la principal complicación trombótica de la EAC. Aproximadamente 9 % de los nuevos casos está constituido por sujetos menores de 45 años. El IAM se produce por el desarrollo de un trombo en el sitio de la placa aterosclerosa, generando oclusión arterial súbita con isquemia y muerte celular. El IAM resulta de la interacción entre factores genéticos y ambientales. Existen diversos factores de riesgo modificables como la hipertensión arterial, la diabetes mellitus, el tabaquismo, la obesidad y la hipercolesterolemia asociados con el IAM. Sin embargo, numerosos pacientes con IAM no presentan factores de riesgo modificables. En la última década se han identificado variantes genéticas en las proteínas relacionadas con los sistemas de coagulación y fibrinólisis, receptores plaquetarios, disfunción endotelial, flujo sanguíneo anormal, metabolismo de la homocisteína, estrés oxidativo, los cuales se asocian a desarrollo del IAM. La identificación de los polimorfismos asociados a la enfermedad arterial coronaria permitirá desarrollar mejores estrategias de tratamiento e identificación de individuos con alto riesgo para EAC y medidas preventivas en etapas tempranas.

BACKGROUND: Coronary artery disease (CAD) is the first cause of death worldwide and represents a public health issue in our country. Acute myocardial infarction (AMI) represents the main thrombotic complication of CAD. Approximately 9% of the new events of MI occur in patients <45 years of age. DISCUSSION: AMI is produced by development of a thrombus at the site of an atherosclerotic plaque that initiates abrupt arterial occlusion, with ischemia and cell death. AMI results from the interaction of gene-environment factors. There are several modifiable factors such as hypertension, diabetes, smoking, obesity, and hypercholesterolemia associated with AMI. However, in a large number of patients with AMI, modifiable risk factors are not present. In the last decade, several genetic variants (polymorphisms) have been identified associated with AMI in genes related to coagulation proteins, fibrinolytic system, platelet receptors, homocysteine metabolism, endothelial dysfunction, abnormal blood flow and oxidative stress. CONCLUSIONS: Identifying the genes associated with CAD will allow us to develop more efficacious treatment strategies and will also help to identify at-risk subjects, thereby enabling the introduction of early preventive measures. Thus, many research efforts continue to address the identification of acquired and inherited risk factors of this complex disease.

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.

Cortical venous thrombosis due to acquired hyperhomocysteinaemia.

A 20-year-old student presented with generalized tonic– clonic seizures and was diagnosed to have cortical venous thrombosis. Her dietary history and the clinical signs of vitamin deficiency prompted further investigations, which detected hyperhomocysteinaemia secondary to vitamin B12 deficiency as a factor contributing to the hypercoagulable state. This case highlights the importance of a balanced diet, as well as the necessity for primordial prevention.

Hiper-homocisteinemia e risco cardiometabólico: [revisão] / Hyperhomocysteinemia and cardiometabolic risk: [review]

A hiper-homocisteinemia, quando considerada como fator causal de doenças vasculares, tem suscitado muitas discussões. Estudos caso-controle, retrospectivos e prospectivos têm identificado relação entre concentrações plasmáticas elevadas de homocisteína e doenças vasculares. Na presente revisão, objetivou-se compreender melhor a inter-relação entre as concentrações plasmáticas de homocisteína e doenças vasculares, além do envolvimento de fatores de risco clássicos para a doença: os genéticos, como as mutações em genes que codificam as enzimas envolvidas no metabolismo da homocisteína, e os nutricionais, como a deficiência de vitaminas do complexo B. Foram consultadas as publicações das principais bases de dados em saúde, no período de 1962 a 2009. O mecanismo pelo qual a hiper-homocisteinemia atua como fator de risco para doenças vasculares ainda não está totalmente esclarecido; entretanto, sugere-se o envolvimento da disfunção endotelial e da peroxidação lipídica. O tratamento da hiper-homocisteinemia fundamenta-se na suplementação alimentar e medicamentosa, com ácido fólico e vitaminas B6 e B12.

Hyperhomocysteinemia, when considered as a causal factor of vascular diseases, has been subject of much discussion. Case-control, retrospective and prospective studies have identified a relationship between high plasma concentrations of homocysteine and vascular disease. The aim of the present review was to better understand the interrelation between plasma concentrations of homocysteine and vascular diseases, as well as the involvement of classical risk factors for the disease: genetic factors, such as mutations in the genes that codify the enzymes involved in the metabolism of homocysteine, and nutritional factors, such as complex B vitamin deficiency. The publications of the main databases in health were consulted for the period 1962 to 2009. The mechanism by which hyperhomocysteinemia acts as a risk factor for vascular diseases still has not been fully clarified, but involvement of endothelial dysfunction and lipid peroxidation is suggested. The treatment of hyperhomocysteinemia is based on food supplements and medication, with folic acid and vitamins B6 and B12.

Prevalence of Hyperhomocysteinemia and Related Factors in a Community-based Health Examination Survey: A Cross-sectional Study / 예방의학회지

BACKGROUND: Many previous studies have shown that elevated homocysteine in the serum is a well known risk factor for cardiovascular disease and this is associated with other risk factors for cardiovascular disease, but any Korean data on this is limited. OBJECTIVES: This study aimed to calculate the prevalence of hyperhomocysteinemia and to analyze the relation between elevated homocysteine and the lifestyle factors of Korean adults. METHODS: We conducted a cross-sectional survey that included 650 men and 743 women (age range, 20 to 79 years) who were residents of Gwangju City in Gyeonggi-do. These subjects participated in the health interview and examination survey from November to December 2005. The total homocysteine, total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride in the serum were measured. All the participants had their body composition measured such as height and weight, and we obtained health-related behavioral information through the self-entry questionnaire. RESULTS: Very right-handed skewed distributions of homocysteine were shown in men and women. The prevalence of hyperhomocysteinemia was 22.6% in men and 13.7% in women in Gwangju city. On the multiple logistic regression analysis, hyperhomocysteinemia was associated with age (OR=1.02, 95% CI=1.01-1.04), male gender (OR=1.60, 95% CI=1.02-2.52), severe general physical activity (OR=0.32, 95% CI=0.15-0.69) and nutrient consumption (OR=0.49, 95% CI=0.31-0.76). CONCLUSIONS: There is a great prevalence of hyperhomocysteinemia in adults of Gwangju City, Korea and it was associated with both genetic factors and lifestyle risk factors. This study can suggest that comprehensive lifestyle modification is needed in order to diminish the prevalence of hyperhomocysteinemia and to prevent CVD.

Obstrução arterial retiniana periférica associada com hiper-homocisteinemia: relato de caso / Peripheral retinal arterial obstruction associated with hyperhomocysteinemia: case report

A hiperhomocisteinemia é fator de risco para fenômenos trombo-embólicos retinianos associados a quadro de oclusão vascular venosa e arterial. Descrevemos um paciente com obstrução arterial retiniana periférica, sem sinais de vasculite ativa, associada a proliferação de neovasos com tração vítreo-retiniana e hemorragia vítrea recidivante. O alto nível sérico de homocisteína decorrente de deficiência de vitamina B12 e ácido fólico, sem outras alterações na cascata da coagulação, inclusive com a pesquisa do fator V de Leiden, sugere que a hiper-homocisteinemia esteja diretamente ligada como fator causal deste quadro clínico. Embora apresentasse PPD elevado, o diagnóstico diferencial mais importante de doença de Eales foi menos considerado por ser diagnóstico de exclusão. O controle do quadro clínico foi feito com suplemento de vitaminas (B12 e ácido fólico) e fotocoagulação retiniana periférica. A homocisteína plasmática total deve ser dosada em pacientes com obstrução vascular retiniana, já que a hiper-homocisteinemia é fator de risco modificável e de fácil tratamento por meio de dieta ou suplementação vitamínica.

Hyperhomocysteinemia is a risk factor for thromboembolic events of the retina associated with vascular venous or arterial occlusion. We describe a patient with occlusion of the peripheral arteriolar network without active vasculitis, associated with neovascular proliferation, peripheral vitreous-retinal traction and relapsing vitreous hemorrhage. The high serum homocysteine level resulting from vitamin B12 and folic acid deficiency, without further changes in the coagulation cascade including the test for Leiden's Factor V, indicates hyperhomocysteinemia as a direct causal factor in this clinical condition. Despite a high PPD, Eales Disease, a major differential diagnosis, was not fully considered, since it is established by exclusion. The patient was treated with photocoagulation and vitamin supplements and the condition was successfully controlled. Patients with retinal vascular obstruction should have their total plasma homocysteine levels measured, since this modifiable risk factor can be easily treated with dietary approaches including vitamin supplementation.

Self-expandable nitinol stent placement in homocysteinemic porcine aorta

PURPOSE: To compare aortic intimal thickening of normal and hyperhomocysteinemic pigs (induced with a methionine-rich diet) following placement of a self-expanding nitinol stent. METHODS: Eighteen Macau pigs were used. They were older than eight weeks in age and had an average weight of 30 kg. Pigs were randomly divided into two groups. The first, Group C (control), was fed a regular diet, and the second group, Group M, was fed a methionine-rich diet for 30 days to induce hyperhomocysteinemia. The self-expandable nitinol stents were 25mm in length and 8 mm in diameter after expansion. Blood samples were collected to measure total cholesterol, triglycerides, HDL and homocysteine concentrations. All animals were subjected to angiography. Thirty days after the procedure, the animals were sacrificed, and the abdominal aorta was removed for histological and digital morphometry analysis. RESULTS: Under microscopic evaluation, the intima was significantly thicker in Group C than in Group M. When groups were compared by digital morphometric analysis, intimal thickening of the vessel wall was higher in Group C than in Group M. There was no significant change in total cholesterol, triglycerides or HDL concentrations in either group. In group C the levels of plasma homocysteine ranged from 14,40 to 16,73µmol/l; in Group M, plasma homocysteine levels ranged from 17.47 to 59.80 µmol/l after 30 days of a methionine-rich diet. CONCLUSION: Compared to normal pigs, less intimal hyperplasia was observed in the abdominal aortas of hyperhomocysteinemic pigs thirty days after the insertion of a self-expandable nitinol stent.

[Study of frequency distribution of homocysteinemia in patients admitted to ICU of Rasoul-Akram hospital 2005]

Homocysteinernia is currently regarded as an independent risk factor in venous thrombosis and vascular diseases. So noticing its causes and risk factors in high risk populations, such as elderly and chronically ill patients is of much importance. This research is designed, considering the important role of homocysteinemia and the lack of statistics and adequate information about the prevalence of this disease among hospitalized patients in ICU. The is a descriptive, cross-sectional study, done by census sampling method on patients admitted in ICU of Rasoul-Akram hospital, during a 6 months period. Epidemiologic data was collected from the patients' files. A blood sample was taken from the patient to measure homocysteine level. Data was introduced using descriptive statistics. 52 patients with the mean age of 58.42 were included in this study. Among these, 12 [23.1%] had a high homocysteine level and the other 40 patients [76.9%] had a normal range of homocysteine. The mean homocysteine level in patients with normal levels was 9.28 [3.08-15.48] micromol/dl and the mean in patients with homocysteinemia was 21.05 [11.05-31.05]. Among patients with homocysteinemia, 25% had renal failure and 25% were presented with cerebrovascular accident [CVA]. There was no significant difference between homocystein level in patients with renal failure and those with CVA. According to the 23.1% frequency of hyperhomocysteinemia in hospitalized patients of our study, also considering the Folate and vitamin B6 and B12 role in homocysteinemia, and also due to previous epidemiologic studies, it seems that evaluating Folate, vitamin B6 and B 12, creatinine clearance and plasma albumin level may clarify the role of these factors as the probable predictive factor in patients with homocysteinemia

Presença de hiper-homocisteinemia em pacientes portadores de três fatores de risco para doença cardiovascular: hipertensão, tabagismo e histórico familiar / The presence of homocysteinemia in patients carrying three risk factors for cardiovascular diseases: hypertension, smoking habit and family history

A hiper-homocisteinemia é um fator de risco independente para desenvolvimento de doença cardiovascular e na presença de outros fatores de risco (FR) poderá acarretar em risco adicional para o surgimento do evento. Foram realizadas dosagens séricas de homocisteína e creatinina em 146 pacientes (51 homens e 95 mulheres) cadastrados no programa HIPERDIA/MS sendo todos portadores de três FR associados: hipertensão, tabagismo e histórico familiar para doença cardiovascular. A média geral foi de 14,48 µmol/L ± 5,98 (15,38 µmol/L ± 6,77 e 13,99 µmol/L ± 5,48, homens e mulheres respectivamente). A hiper-homocisteinemia esteve presente em 34,90% (39,20% e 32,60%, homens e mulheres respectivamente), de acordo com o intervalo de referência entre 5 - 15 µmol/L. Entretanto, segundo recomendações da DACH-LIGA Homocysteine, valores entre 12 - 30 µmol/L são considerados como moderada hiper-homocisteinemia. O estudo revelou que 60,30% (70,60% e 54,70%, homens e mulheres respectivamente) estavam acima de 12 µmol/L. Na avaliação do estudo, a dosagem de homocisteína sérica deve ser realizada em pacientes cadastrados no programa HIPERDIA/MS, pois além de hipertensos e/ou diabéticos, a presença de hiper-homocisteinemia pode ser um risco adicional para o desenvolvimento de doença cardiovascular.

Hiper-homocysteinemia is an independent risk factor in the development of cardiovascular diseases and in the presence of other risk factors (RF) may bring about an additional risk for the occurrence of the event. Serum dosages of homocysteine and creatinine in 146 patients (51 men and 95 women), registered at the HIPERDIA/MS Program, all presenting three associated RF's; hypertension, smoking habit and family history for cardiovascular diseases. The general average has been 14.48 µmol/L ± 5,98 (15,38 µmol/L ±6,77 and 13,99 µmol/L ± 5,48, for men and women respectively). Hiper-homocysteinemia had been present in 34.90% (39.20% and 32.60%, men and women, respectively), according to the reference interval between 5 - 15 µmol/L. Although, according to Homocysteine DACH-LIGA recommendations, values between 12 - 30 µmol/L are considered being a moderate hiper-homocysteinemia. The study has revealed that 60.30% (70.60% and 54.70%, men and women, respectively) had been above 12 µmol/L. In the evaluation of the study, the serum dosage of homocysteine has to be performed in patients registered at the HIPERDIA/MS Program for, besides being hypertense and/or diabetic, the presence of hiper-homocisteinemia may be an additional risk for the development of cardiovascular disease.

Homocistéina e metilenotetrahidrofolato redutase em indivíduos submetidos à angiografia coronariana / Homocysteine and methylenetetrahydrofolate reductase in subjects undergoing coronary angiography

OBJETIVO: Determinar os níveis plasmáticos de homocisteína e a incidência do polimorfismo C677T no gene da enzima metilenotetrahidrofolato redutase (MTHFR) em um grupo de indivíduos submetidos a angiografia coronariana, buscando estabelecer a possível correlação entre esses parâmetros e a gravidade da doença arterial coronariana (DAC), bem como investigar a correlação entre hiper-homocisteinemia e a presença do polimorfismo. MÉTODOS: Vinte indivíduos com ausência de ateromatose nas coronárias (controles), quatorze indivíduos apresentando ateromatose leve/moderada e vinte e nove indivíduos apresentando ateromatose grave foram avaliados. RESULTADOS: Para o parâmetro homocisteína foram observadas diferenças significativas entre as médias dos grupos controle e ateromatose grave (p < 0,001). Entre os demais grupos não foram observadas diferenças significativas. O grupo ateromatose grave apresentou uma freqüência de 62,0 por cento e 6,9 por cento para o polimorfismo C677T no gene da enzima MTHFR, em heterozigose e homozigose, respectivamente. Entretanto, não foi observada correlação entre a presença da mutação e hiper-homocisteinemia. Foi observada uma correlação positiva da ordem de 41,91 por cento (p < 0,001) entre hiper-homocisteinemia e a presença de DAC. CONCLUSÃO: O achado mais importante deste estudo foi a associação entre hiper-homocisteinemia e a presença de estenose coronariana superior a 70 por cento; entretanto, permanece a dúvida se o aumento da concentração plasmática de homocisteína constitui um fator determinante para o agravamento da lesão aterosclerótica nas coronárias ou se o mesmo é uma conseqüência desta lesão.

OBJECTIVE: To determine plasma homocysteine levels and the incidence of methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD), as well as investigate the correlation between hyperhomocysteinemia and the presence of polymorphism. METHODS: Twenty subjects with no coronary atheromatosis (controls), fourteen subjects with mild/moderate atheromatosis, and twenty-nine subjects with severe atheromatosis were evaluated. RESULTS: Significant differences were observed in mean homocysteine levels between the control and the severe atheromatosis groups (p < 0.001). No significant differences were observed among the other groups. The severe atheromatosis group showed rates of 62.0 percent and 6.9 percent for the C677T MTHFR gene polymorphism, in heterozygous and homozygous subjects, respectively. However, there was no correlation between the presence of mutation and hyperhomocysteinemia. A positive correlation of 41.91 percent (p < 0.001) was found between hyperhomocysteinemia and CAD. CONCLUSION: The most important finding of this study was the association between hyperhomocysteinemia and coronary stenosis > 70 percent; yet, whether elevated plasma homocysteine worsens atherosclerosis or is a consequence remains to be established.