Voluntary Exercise Attenuates Hyperhomocysteinemia, But Does not Protect Against Hyperhomocysteinemia-Induced Testicular and Epididymal Disturbances.

The hyperhomocysteinemia (HHcy) is toxic to the cells and associated with several diseases. Clinical studies have shown changes in plasma concentrations of Hcy after physical exercise. This study aimed to assess the effect of HHcy on testis, epididymis and sperm quality and to investigate whether voluntary exercise training protects this system against damage caused by HHcy in Swiss mice. In this study, 48 mice were randomly distributed in the control, HHcy, physical exercise, and HHcy combined with physical exercise groups. HHcy was induced by daily administration of dl-homocysteine thiolactone via gavage throughout the experimental period. Physical exercise was performed through voluntary running on the exercise wheels. The plasma concentrations of homocysteine (Hcy) and testosterone were determined. The testes and epididymis were used to assess the sperm count, histopathology, lipoperoxidation, cytokine levels, testicular cholesterol, myeloperoxidase, and catalase activity. Spermatozoa were analyzed for morphology, acrosome integrity, mitochondrial activity, and motility. In the testes, HHcy increased the number of abnormal seminiferous tubules, reduced the tubular diameter and the height of the germinal epithelium. In the epididymis, there was tissue remodeling in the head region. Ultimately, voluntary physical exercise training reduced plasma Hcy concentration but did not attenuate HHcy-induced testicular and epididymal disturbances.

The serum homocysteine level in patients with acute ischemic stroke (AIS) after thrombolysis and its relationship with clinical outcomes.

OBJECTIVE: The present study aims to investigate whether hyperhomocysteinemia (HHcy) affects the outcomes of the thrombolytic treatment for patients with AIS. METHODS: A sample of 120 AIS patients were recruited and grouped according to their serum homocysteine (Hcy) levels. The National Institute of Health Stroke Scale (NIHSS) was obtained before treatment and 7 days after it to evaluate neurological outcomes; modified Rankin Scale (mRS) was obtained 12 weeks later to assess functional outcomes. Receiver operating characteristic curve (ROC) was used to demonstrate the relationship between serum Hcy level and the outcomes after tPA treatment. RESULTS: The serum Hcy level of 120 patients was of 27.57±20.17µmol/L. The NIHSS scores of the patients in the low Hcy level group were remarkably lower compared to those in the high-level group (p<0.05), after 7 days of treatment. In addition, the mRS scores of the patients in the low Hcy level group, after 12 weeks, were remarkably lower compared to those in the high-level group (p<0.01). ROC demonstrated that the serum Hcy level is related to the clinical outcomes of thrombolytic treatment with moderate specificity (80.3%) and sensitivity (58.2%). CONCLUSION: In conclusion, higher serum Hcy levels can indicate poorer clinical outcomes of thrombolytic treatment in patients with AIS.

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis.

The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 µmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p < 0.001), tumor necrosis factor alpha (TNF-α, p < 0.001), TNF receptor 1 (TNFR1, p = 0.038), TNF receptor 2 (TNFR2, p < 0.001), and lower levels of PECAM (p = 0.001), ICAM (p < 0.001) and VCAM (p = 0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p < 0.001), disability evaluated by Expanded Disability Status Score EDSS (p < 0.001), TNFR1 (p = 0.039) and ICAM (p = 0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p < 0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.

The serum homocysteine level in patients with acute ischemic stroke (AIS) after thrombolysis and its relationship with clinical outcomes

SUMMARY OBJECTIVE The present study aims to investigate whether hyperhomocysteinemia (HHcy) affects the outcomes of the thrombolytic treatment for patients with AIS. METHODS A sample of 120 AIS patients were recruited and grouped according to their serum homocysteine (Hcy) levels. The National Institute of Health Stroke Scale (NIHSS) was obtained before treatment and 7 days after it to evaluate neurological outcomes; modified Rankin Scale (mRS) was obtained 12 weeks later to assess functional outcomes. Receiver operating characteristic curve (ROC) was used to demonstrate the relationship between serum Hcy level and the outcomes after tPA treatment. RESULTS The serum Hcy level of 120 patients was of 27.57±20.17μmol/L. The NIHSS scores of the patients in the low Hcy level group were remarkably lower compared to those in the high-level group (p<0.05), after 7 days of treatment. In addition, the mRS scores of the patients in the low Hcy level group, after 12 weeks, were remarkably lower compared to those in the high-level group (p<0.01). ROC demonstrated that the serum Hcy level is related to the clinical outcomes of thrombolytic treatment with moderate specificity (80.3%) and sensitivity (58.2%). CONCLUSION In conclusion, higher serum Hcy levels can indicate poorer clinical outcomes of thrombolytic treatment in patients with AIS.

RESUMO OBJETIVO O presente estudo tem por objetivo investigar se a hiperhomocisteinemia (HHcy) afeta os resultados do tratamento trombolítico em pacientes com AVCI agudo. METODOLOGIA Uma amostra de 120 pacientes AVCI agudo foi recrutada e agrupada de acordo com os níveis séricos de homocisteína (Hcy). Uma avaliação nos padrões do National Institute of Health Stroke Scale (NIHSS) foi obtida antes do tratamento e 7 dias após ele para avaliar desfechos neurológicos e a escala de Rankin modificada foi utilizada 12 semanas depois para avaliar os desfechos funcionais. A curva ROC (Receiver Operating Caracteristic) foi utilizada para demonstrar a relação entre os níveis séricos de Hcy e os desfechos após tratamento com t-PA. RESULTADOS Os níveis séricos de Hcy de 120 pacientes foi de 27,57±20,17μmol/L. Os escores NIHSS dos pacientes no grupo de baixo nível de Hcy foram notavelmente mais baixos em comparação àqueles do grupo de nível mais alto (p<0,05), após 7 dias de tratamento. Além disso, os escores mRS dos pacientes no grupo de baixo nível de Hcy, após 12 semanas, foram consideravelmente mais baixos em comparação com os do grupo de alto nível (p<0,01). A curva ROC demonstrou que o nível sérico de Hcy tem relação com os desfechos clínicos do tratamento trombolítico com especificidade moderada (80,3%) e sensibilidade (58,2%). CONCLUSÃO Podemos concluir então que níveis séricos mais altos de Hcy podem prever desfechos clínicos piores para o tratamento trombolítico em pacientes com AVCI agudo.

Thrombotic microangiopathy caused by methionine synthase deficiency: diagnosis and treatment pitfalls.

BACKGROUND: Inborn errors of cobalamin (Cbl) metabolism form a large group of rare diseases. One of these, Cbl deficiency type C (CblC), is a well-known cause of thrombotic microangiopathy (TMA), especially in infants. However, there has only been a single published case of TMA associated to Cbl deficiency type G (CblG), also known as methionine synthase deficiency (MSD). CASE DIAGNOSIS/TREATMENT: A 21-month-old boy presented with pallor and oral ulcers during episodes of upper respiratory infection (URI). Further examination revealed signs of TMA, and the patient progressed to acute renal failure (ARF). Renal biopsy showed TMA. Evaluation for infection and autoantibodies were negative. The C3 and C4 complement fractions were normal. Analysis of the bone marrow aspirate suggested megaloblastic anemia and signs of hematopoiesis activation (secondary to peripheral hemolysis). Although the serum vitamin B12 level was normal, the patient was treated with cyanocobalamin, with no improvement. The ARF and hematologic parameters improved with conservative treatment. A severe relapse occurred during the follow-up, with normal ADAMTS13 activity. The presumed diagnosis was atypical hemolytic uremic syndrome, and the patient was started on eculizumab, but his response was poor, even when the dosage was increased. At this point it was also recognized that his developmental speech was delayed. Based on these findings, whole exome sequencing was performed, leading to the detection of two novel deleterious variants in the gene coding for methionine synthase, confirming the diagnosis of MSD. Subsequent treatment consisted of elevating the patient's serum homocysteine level and starting him on hydroxicobalamin, with normalization of all hematologic parameters although the microalbuminuria remained. CONCLUSIONS: Methionine synthase deficiency is very rare and characterized by megaloblastic anemia and neurological symptoms. We report the second case of MSD associated to TMA previously diagnosed as aHUS in which the patient had a poor response to eculizumab.

Folic acid and autism: What do we know?

Autism spectrum disorders (ASD) consist in a range of neurodevelopmental conditions that share common features with autism, such as impairments in communication and social interaction, repetitive behaviors, stereotypies, and a limited repertoire of interests and activities. Some studies have reported that folic acid supplementation could be associated with a higher incidence of autism, and therefore, we aimed to conduct a systematic review of studies involving relationships between this molecule and ASD. The MEDLINE database was searched for studies written in English which evaluated the relationship between autism and folate. The initial search yielded 60 potentially relevant articles, of which 11 met the inclusion criteria. The agreement between reviewers was κ = 0.808. The articles included in the present study addressed topics related to the prescription of vitamins, the association between folic acid intake/supplementation during pregnancy and the incidence of autism, food intake, and/or nutrient supplementation in children/adolescents with autism, the evaluation of serum nutrient levels, and nutritional interventions targeting ASD. Regarding our main issue, namely the effect of folic acid supplementation, especially in pregnancy, the few and contradictory studies present inconsistent conclusions. Epidemiological associations are not reproduced in most of the other types of studies. Although some studies have reported lower folate levels in patients with ASD, the effects of folate-enhancing interventions on the clinical symptoms have yet to be confirmed.

Whey protein supplementation increases methionine intake but not homocysteine plasma concentration in rats.

The purpose of this study was to examine the effects of whey protein supplementation on homocysteine (Hcy) metabolism and liver oxidative stress in rats. Twenty-four rats were divided into 3 groups (n = 8) to receive one of the following diets for 4 weeks: control diet (C), whey protein-composed diet (WP), and whey protein-supplemented diet (WPS). The C and WP diets consisted of AIN-93 with 20% casein and 20% whey protein as protein source, respectively. WPS was AIN-93 (20% casein) supplemented by the addition of 20% (w/w) whey protein. Four weeks of ingesting a WPS diet resulted in a significantly higher (P < 0.05) total protein and methionine intakes. Although a significant increase (P < 0.05) in the hepatic S-adenosylmethionine and S-adenosylhomocysteine levels occurred in WPS group compared with C and WP, no significant change was observed in plasma Hcy concentration between groups. Furthermore, the levels of lipid hydroperoxides and advanced oxidation protein products, known liver oxidative stress markers, were increased in the WPS group compared with the C group. In addition, no change in glutathione liver concentration was observed in any of the groups studied. In conclusion, whey protein supplementation increases methionine intake substantially; however, it does not change plasma Hcy concentrations. On the other hand, increased hepatic oxidative stress markers were observed in whey protein supplemented rats were probably due to high protein intake.

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.

Comparison of homocysteinemia and MTHFR 677CT polymorphism with Framingham Coronary Heart Risk Score.

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.

Does phase angle correlate with hyperhomocysteinemia? A study of patients with classical homocystinuria.

The role of the phase angle in hyperhomocysteinemia has yet to be assessed. Classical homocystinuria is a rare genetic disease characterized by severe hyperhomocysteinemia, as well as increased levels of methionine and reduced levels of cysteine. The objective of this study was to investigate the potential relationship between phase angle and homocysteine, cysteine, and methionine levels in patients with classical homocystinuria. Eight patients were included in the study. Phase angle was measured with a tetrapolar bioimpedance analyzer. Serum homocysteine, cysteine, and methionine levels were measured by HPLC. Only three patients had adequate metabolic control of their disease. Median phase angle was 5.9° (range = 5.4°-8.5°). There was a significant correlation between phase angle and levels of homocysteine (r = -0.807, p = 0.015), methionine (r = -0.711, p = 0.048), and cysteine (r = 0.836, p = 0.010). Was also positively correlated with BMI and arm muscle circumference (p < 0.05). Two patients had phase angles below the 5th percentile, and only one above the 50th percentile. Our findings suggest that cellular integrity is affected in patients with high homocysteine levels, thus indicating that phase angle could be a valuable indicator of prognosis and classical homocystinuria. It also suggests a role for this indicator in other forms of hyperhomocysteinemia and other inborn errors of metabolism.

Chronic hyperhomocysteinemia increases inflammatory markers in hippocampus and serum of rats.

This study investigated the effects of chronic homocysteine administration on some parameters of inflammation, such as cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1), nitrite and prostaglandin E(2) levels, as well as on immunocontent of NF-κB/p65 subunit in hippocampus and/or serum of rats. Since acetylcholinesterase has been associated with inflammation, we also evaluated the effect of homocysteine on this enzyme activity in hippocampus of rats. Wistar rats received daily subcutaneous injections of homocysteine (0.3-0.6 µmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12 h after the last injection, rats were euthanized and hippocampus and serum were used. Results showed that chronic hyperhomocysteinemia significantly increased pro-inflammatory cytokines (TNF-α, IL-1ß and IL-6), chemokine CCL(2) (MCP-1) and prostaglandin E(2) in hippocampus and serum of rats at 1 and 12 h after the last injection of homocysteine. Nitrite levels increased in hippocampus, but decreased in serum at 1 h after chronic hyperhomocysteinemia. Acetylcholinesterase activity and immunocontent of citoplasmic and nuclear NF-κB/p65 subunit were increased in hippocampus of rats subjected to hyperhomocysteinemia at 1 h, but did not alter at 12 h after the last injection of homocysteine. According to our results, chronic hyperhomocysteinemia increases inflammatory parameters, suggesting that this process might be associated, at least in part, with the cerebrovascular and vascular dysfunctions characteristic of some homocystinuric patients.

Acute hyperhomocysteinemia alters the coagulation system and oxidative status in the blood of rats.

In the present study, we investigated the effect of the acute administration of homocysteine (Hcy) on parameters of the coagulation system, as well as fibrinogen and nitrite levels in the blood of rats. In addition, we evaluated the effect of acute hyperhomocysteinemia on thiobarbituric acid-reactive substances in plasma and on antioxidant enzymes activities (superoxide dismutase, catalase, and gluthatione peroxidase) in the erythrocytes of rats. Wistar rats, aged 29 days, received a single subcutaneous dorsal injection of saline (control) or Hcy (0.6 µmol/g body weight). Fifteen minutes, 1 h, 6 h or 12 h after the injection, the rats were euthanized and the blood, plasma, and erythrocytes were collected. Results showed that Hcy significantly increased platelet count in the blood and plasma fibrinogen levels of rats at 15 min and 1 h, but not at 6 h and 12 h, when compared with the control group. Prothrombin time, activated partial thromboplastin time, and nitrite levels significantly decreased in plasma at 15 min and 1 h, but not at 6 h and 12 h after Hcy administration. In addition, hyperhomocysteinemia increased thiobarbituric acid-reactive, an index of lipid peroxidation, in plasma at 15 min and 1 h; decreased the superoxide dismutase and gluthatione peroxidase activity, and increased the catalase activity at 15 min in erythrocytes of rats, suggesting that acute Hcy administration may alter the oxidative status in the blood of rats. Our findings suggest that hypercoagulability and oxidative stress can occur after acute hyperhomocysteinemia, possibly in association, at least in part, with the vascular dysfunction and thromboembolic complications observed in homocystinuric patients.

Fortification of flours with folic acid reduces homocysteine levels in Brazilian women.

Our hypothesis is that the fortification of flour with folic acid contributes to the reduction of plasma homocysteine (Hcy). We conducted a cross-sectional study covering 2 periods, before and after fortification (2002-2003 and 2008-2009, respectively), to assess the influence of the consumption of corn and wheat flours prefortification and postfortification with folic acid on Hcy levels and other biomarkers. In the total, 93 women (38 prefortification and 55 postfortification) were included. Levels of lipids and glucose, total Hcy and serum folate, and cobalamin were determined using commercial kits by colorimetric method, competitive immunoassay, and chemiluminescence, respectively The participants' average age was 48.1 ± 9.5 years for the prefortification group and 39.1 ± 4.1 years for the postfortification group (P < .001) but adjusted statistical tests by age. Both groups presented obesity class 1. In the prefortification group, 71.1% (n = 27) of women had a dietary intake of folate, which was lower than the current recommended for adults (< 400 µg/d), whereas in the postfortification group, only 16.4% (n = 9) of women had lower intakes than recommended. In the prefortification group, 42.1% (n = 16) of women had hyperhomocysteinemia (> 10 mmol/L) compared with only 9.1% (n = 5) in the postfortification group. Moreover, statistically significant differences were found between the 2 groups in total cholesterol, high-density lipoprotein, triglycerides, and dietary fiber. Our findings corroborate the hypothesis that fortification of wheat and corn flours with folic acid can possibly be associated with lower concentrations of plasma Hcy, providing probable greater cardiovascular protection in this group.

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

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

Impaired fibrin gel permeability by high homocysteine levels.

Mechanisms involved in the relationship between hyperhomocysteinemia and thrombosis are still unclear. In previous reports we have shown that high homocysteine concentrations led to more compact and branched fibrin networks than controls. These clots showed an impaired lysis associated to their architecture. The aim of this study was to evaluate the effects of homocysteine on permeation of clots obtained from plasma and purified systems. Fibrin gels were prepared with normal plasma incubated with homocysteine and, in the purified systems, with fibrinogen and factor XIII treated with the amino acid. Permeability constants (K(s)) were determined through flow measurements. Linear regression curve between K(s) values and homocysteine levels in the plasmatic assays showed a negative correlation coefficient, r = -0.997 (p = 0.003). K(s) of fibrin gels obtained from purified systems with fibrinogen incubated with homocysteine was (7.07 ± 0.27) × 10(-9) cm(2), control was (11.40 ± 0.37) × 10(-9) cm(2) (n = 3; p < 0.01). K(s) of fibrin gels obtained with factor XIII treated with homocysteine was (1.47 ± 0.17) × 10(-9) cm (2), and control was (3.31 ± 0.31) × 10(-9) cm(2) (n = 3; p<0.01). Plasma incubated with high homocysteine concentrations produced fibrin clots significantly less permeable than controls in a dose dependent manner, and the results showed that fibrinogen and factor XIII were involved in that detrimental effect. These findings might explain the impaired fibrinolysis related to increased homocysteine levels and contribute to understanding the association between the amino acid and thrombosis.

Mutations in methylenetetrahydrofolate reductase and in cysthationine beta synthase: is there a link to homocysteine levels in peripheral arterial disease?

Peripheral arterial disease (PAD) is an atherosclerotic disturbance characterized by a progressive obstruction of lower limb arteries. Many risk factors associated with PAD development have being reported in the literature. The present study aimed to investigate whether mutations in the methylenetetrahydrofolate reductase (MTHFR) or in the cystathionine beta synthase (CBS) genes are associated with higher levels of homocysteine and the risk of PAD in patients from Brazil. This study analyzed 39 patients with PAD and 32 without PAD in whom risk factors and C677T mutations in the MTHFR gene and both 844ins68 and T833C mutations in the CBS gene were investigated. Although higher levels of homocysteine could be observed in patients with PAD compared to controls, no association between the increase of homocysteine and the frequency of C677T, 844ins68, and T833C mutations could be observed. The results suggest that these mutations do not appear to be related to either homocysteine levels or the development of the disease. However, hyperhomocysteinemia and smoking are important factors in PAD development.

Genetic factors of the hemostatic system in young patients with myocardial infarction.

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.

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.

Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson's disease.

In the present work we measured blood levels of total homocysteine ((t)Hcy), vitamin B(12) and folic acid in patients with Parkinson s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma (t)Hcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of (t)Hcy in PD patients was folic acid deficiency, whereas in controls (t)Hcy levels were mainly determined by plasma vitamin B(12) concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma (t)Hcy, folic acid and vitamin B(12) levels in parkinsonians. Furthermore, disease duration was positively associated with (t)Hcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder.

Hyperhomocysteinaemia-induced cardiovascular changes in rats.

(1) Increased plasma homocysteine content and increased blood pressure are independently associated with higher cardiovascular risks. The present study was designed to determine the effects of hyperhomocysteinaemia (HHcys) on the activity of the cardiovascular system in rats. (2) Using male Wistar rats, the effect of moderate HHcys, induced by treating rats with dl-homocysteine thiolactone (DL-HT; 1 g/kg per day) for 15 days, on arterial blood pressure, heart rate, baroreflex and vascular reactivity was determined. (3) Hyperhomocysteinaemia was observed after 15 days of treatment. Baseline arterial blood pressure and heart rate values of HHcys animals were significantly increased after 15 days of treatment. Plasma homocysteine and cardiovascular parameters returned to control values after termination of treatment. Baroreflex gain was significantly enhanced in HHcys rats. The pressor effect of an i.v. infusion of phenylephrine (50 mg/kg per mL) was decreased in HHcys rats and returned to control values after washout of DL-HT. Hypotensive responses to i.v. infusions of sodium nitroprusside (70 mg/kg per mL) or acetylcholine (10 mg/kg per mL) were increased in HHcys animals and returned to control values after washout of DL-HT. The increase in resting arterial blood pressure associated with the moderate HHcys was reversed by treatment with the b1-adrenoceptor antagonist atenolol, suggesting that HHcys-related hypertension is related to increase in cardiac sympathetic activity. (4) The present study showed significantly increased arterial blood pressure, heart rate and baroreflex activity in the early phase of moderate HHcys. In addition, HHcys was associated with alterations of vascular responsiveness to pressor and depressor agents, as well as increased cardiac sympathetic activity. The fact that cardiovascular changes observed in HHcys were reversed after DL-HT washout indicate that moderate HHcys evokes cardiovascular changes.