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Total homocysteine and cardiovascular disease
Abstract
Nygård O, Vollset SE, Refsum H, Brattström L, Ueland PM (University of Bergen, Norway; County Hospital, Kalmar, Sweden). Total homocysteine and cardiovascular disease (Review). J Intern Med 1999; 246: 425–454.
Recent data have shown that an elevated plasma level of the amino acid homocysteine (Hcy) is a common, independent, easily modifiable and possibly causal risk factor for cardiovascular disease (CVD) which may be of equal importance to hypercholesterolemia, hypertension and smoking. This paper reviews the biochemical, clinical, epidemiological and experimental data underlying this conclusion and is critically questioning whether elevated tHcy is a causal factor.
... Los efectos fisiopatológicos de la Hcy no han sido comprendidos completamente. Uno de los mecanismos propuestos es que la oxidación de la Hcy genera los aniones superóxido y peróxido de hidrógeno y se desencadena el estrés oxidativo; el otro mecanismo es el aumento en la adhesión de los leucocitos, el incremento de la actividad de los factores de coagulación, de la agregación plaquetaria y se reduce la fibrinolísis (12,21,22). ...
... Elevados niveles de Hcy han sido asociados con daño endotelial en muchos estudios in vivo e in vitro, los datos sugieren que la Hcy tiene un efecto citotóxico en las células endoteliales (21). ...
... De la misma forma se ha sugerido que los elevados niveles de Hcy reducen la capacidad de dilatación vascular, a través de la disminución de la relación elastina/colágeno y de la activación de la enzima gelatinasa elastinolítica. Consecuentemente se da un daño en la estructura vascular y un incremento en su resistencia, lo que desencadena hipertensión (21,22,28). ...
de Framingham reconoció la homocisteína (Hcy) como un posible factor de riesgo para enfermedad cardiovascular (ECV) y en el año 2003 lo declaró como factor de riesgo "emergente". La hiperhomocisteinemia se define como el aumento de los niveles plasmáticos de Hcy total (unida a proteínas más fracción libre), por encima de 15 μmol/L y se clasifica en tres niveles de severidad, moderado de 15-30 μmol/L, intermedio de 31-100 μmol/L y severo mayor de 100 μmol/L. La hiperhomocisteinemia puede producirse por una deficiencia enzimática en alguno de los pasos de su metabolismo, también se puede presentar por bajos niveles plasmáticosdel ácido fólico y las vitaminas B6 y/o B12. La insuficiencia renal puede ser otra causa, debido a que el riñón es la ruta para eliminar la Hcy del plasma. La suplementación dietaria con ácido fólico reduce lasconcentraciones de Hcy en sangre en un 25%, la suplementación con vitamina B12 en un 7%, mientras que la suplementación con vitamina B6 no tiene efecto en esta disminución. Un estilo de vida saludable, una dieta balanceada con un moderado consumo de café y alcohol y dejar de fumar, contribuye en la reducción de los niveles plasmáticos de Hcy.
... The balance between MMP and TIMP is vital for correctly functioning ECM remodeling and is required for various developmental and morphogenetic processes [74]. In this direction, Refsum et al. [75] reported a considerable rise in the expression of MMP-9 and a reduction in the expression of its tissue inhibitor TIMP-2. The increased MMP-9 protein/mRNA levels destroy tight junction proteins (TJPs) and improve BBB permeability [75]. ...
... In this direction, Refsum et al. [75] reported a considerable rise in the expression of MMP-9 and a reduction in the expression of its tissue inhibitor TIMP-2. The increased MMP-9 protein/mRNA levels destroy tight junction proteins (TJPs) and improve BBB permeability [75]. TJPs are critical not just for tissue integrity, but also for vascular permeability, leukocyte extravasation, and angiogenesis [76]. ...
... TJPs control BBB function and keep MPT pores closed, providing them with neuroprotective characteristics. Mondal et al. [75] found that MMP-9 activation is related to reduced expression of cellular TJPs, zonula оccludens-1 (ZO1), and occludin (in both protein and mRNA levels), which leads to mitophagy. These findings reveal that mitochondrial dysfunction in the ischemic brain downregulates ZO1 and occludin, mitigated by THC treatment. ...
Tetrahydrocurcumin (THC), one of the major metabolites of CUR, possesses several CUR-like pharmacological effects; however, its mechanisms of action are largely unknown. This manuscript aims to summarize the literature on the preventive role of THC on vascular dysfunction and the development of hypertension by exploring the effects of THC on hemodynamic status, aortic elasticity, and oxidative stress in vasculature in different animal models. We review the protective effects of THC against hypertension induced by heavy metals (cadmium and iron), as well as its impact on arterial stiffness and vascular remodeling. The effects of THC on angiogenesis in CaSki xenografted mice and the expression of vascular endothelial growth factor (VEGF) are well documented. On the other hand, as an anti-inflammatory and antioxidant compound, THC is involved in enhancing homocysteine-induced mitochondrial remodeling in brain endothelial cells. The experimental evidence regarding the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion injury and the therapeutic potential of THC to alleviate mitochondrial cerebral dysmorphic dysfunction patterns is also scrutinized and explored. Overall, the studies on different animal models of disease suggest that THC can be used as a dietary supplement to protect against cardiovascular changes caused by various factors (such as heavy metal overload, oxidative stress, and carcinogenesis). Additionally, the reviewed literature data seem to confirm THC’s potential to improve mitochondrial dysfunction in cerebral vasculature during ischemic stroke through epigenetic mechanisms. We suggest that further preclinical studies should be implemented to demonstrate THC’s vascular-protective, antiangiogenic, and anti-tumorigenic effects in humans. Applying the methods used in the presently reviewed studies would be useful and will help define the doses and methods of THC administration in various disease settings.
... The TT genotype is homozygous in only around 12% of the white population (Brattström et al. 1998). According to several studies (CC genotype), TT homozygotes have a plasma homocysteine content of _3.5 _mol/L, or 35% greater than wild-type homozygotes (CC genotype) (Nygård et al. 1999). High plasma homocysteine concentrations are only identified in those with low serum or plasma folate levels. ...
... High plasma homocysteine concentrations are only identified in those with low serum or plasma folate levels. The homocysteine levels in these TT homozygotes are even higher than the ones listed above (Nygård et al. 1999). With plasma homocysteine concentrations >18 mol/L, the TT genotype is found in _30% of the population; with homocysteine values >40 mol/L, _70% of the population is homozygous for the TT genotype (Brattström et al. 1998). ...
... Given that the TT genotype is present from birth and adult dietary choices do not change over time, TT homozygotes with low folate intakes should be exposed to muchelevated plasma homocysteine levels for decades. As a result, over 40 studies, including thousands of cardiovascular patients and controls, have been done in recent years to determine whether the TT genotype is associated with an increased risk or severity of artery disease (Anderson et al. 1997;Arai et al. 1997;Brattström et al. 1998;Girelli et al. 1998;Morita et al. 1998;Verhoef et al. 1998;Dunn et al. 1998;Nakata et al. 1998;Fijnheer et al. 1998;MALIK et al. 1998;Verhoeff et al. 1998;Salooja et al. 1998;Demuth et al. 1998;Thuillier et al. 1998;Lalouschek et al. 1999a;McQuillan et al. 1999;Lalouschek et al. 1999b;Harmon et al. 1999;Press et al. 1999;Gardemann et al. 1999;Spence et al. 1999;Tokgözoğlu et al. 1999;Nygård et al. 1999). Even in the presence of inadequate folate status, hyperhomocysteinemia associated with the TT genotype appears to be benign and unrelated to the risk or severity of cardiovascular disease, according to the findings of these studies ). ...
Homocysteine is a methyl group metabolic intermediate that requires numerous B-vitamin cofactors in the diet to function properly. The relationship between homocysteine metabolism and health and disease is becoming more well-known. Homocysteine metabolism disturbances, primarily intracellular and subsequent circulatory homocysteine buildup (hyperhomocysteinemia), are linked to vascular disease risk and other diseases. On the other hand, B-vitamin treatment has successfully restored average homocysteine concentrations without corresponding decreases in disease risk. As a result, researchers are still investigating the molecular link between homocysteine equilibrium and disease states and the efficacy of homocysteine regulation.
... The TT genotype is homozygous in only around 12% of the white population (Brattström et al. 1998). According to several studies (CC genotype), TT homozygotes have a plasma homocysteine content of _3.5 _mol/L, or 35% greater than wild-type homozygotes (CC genotype) (Nygård et al. 1999). High plasma homocysteine concentrations are only identified in those with low serum or plasma folate levels. ...
... High plasma homocysteine concentrations are only identified in those with low serum or plasma folate levels. The homocysteine levels in these TT homozygotes are even higher than the ones listed above (Nygård et al. 1999). With plasma homocysteine concentrations >18 mol/L, the TT genotype is found in _30% of the population; with homocysteine values >40 mol/L, _70% of the population is homozygous for the TT genotype (Brattström et al. 1998). ...
... Given that the TT genotype is present from birth and adult dietary choices do not change over time, TT homozygotes with low folate intakes should be exposed to muchelevated plasma homocysteine levels for decades. As a result, over 40 studies, including thousands of cardiovascular patients and controls, have been done in recent years to determine whether the TT genotype is associated with an increased risk or severity of artery disease (Anderson et al. 1997;Arai et al. 1997;Brattström et al. 1998;Girelli et al. 1998;Morita et al. 1998;Verhoef et al. 1998;Dunn et al. 1998;Nakata et al. 1998;Fijnheer et al. 1998;MALIK et al. 1998;Verhoeff et al. 1998;Salooja et al. 1998;Demuth et al. 1998;Thuillier et al. 1998;Lalouschek et al. 1999a;McQuillan et al. 1999;Lalouschek et al. 1999b;Harmon et al. 1999;Press et al. 1999;Gardemann et al. 1999;Spence et al. 1999;Tokgözoğlu et al. 1999;Nygård et al. 1999). Even in the presence of inadequate folate status, hyperhomocysteinemia associated with the TT genotype appears to be benign and unrelated to the risk or severity of cardiovascular disease, according to the findings of these studies ). ...
Homocysteine AQ2 is a methyl group metabolism intermediate that relies on many B-vitamin cofactors in the diet. The relationship between homocysteine metabolism and health and disease is becoming more well-known. Homocysteine metabolism disturbances, primarily intracellular and subsequent circulatory homocysteine buildup (hyperhomocysteinemia), are linked to vascular disease risk and other diseases.
On the other hand, B-vitamin treatment has successfully restored average homocysteine concentrations without corresponding decreases in disease risk. As a result, researchers are still investigating the molecular link between homocysteine equilibrium and disease states and the efficacy of homocysteine regulation.
... 10 It can be recycled into methionine or converted to cysteine in the presence of vitamin cofactors like folic acid (vitamin B9) majorly, pyridoxal phosphate (vitamin B6), cyanocobalamin (vitamin B12) and riboflavin (vitamin B2) to a lesser extent. [11][12][13] Enzymes such as methylene tetrahydrofolate reductase (MTHFR) and cystathionine-β-synthase are also required in the process. 11 Studies have documented that deficiencies of vitamin cofactors and inherited enzyme deficiency or mutation predispose to hyperhomocysteinaemia which has been shown to be associated with endothelial injury and consequently raised blood pressure. ...
... [11][12][13] Enzymes such as methylene tetrahydrofolate reductase (MTHFR) and cystathionine-β-synthase are also required in the process. 11 Studies have documented that deficiencies of vitamin cofactors and inherited enzyme deficiency or mutation predispose to hyperhomocysteinaemia which has been shown to be associated with endothelial injury and consequently raised blood pressure. [11][12][14][15] It has also been reported that vitamin supplementation can reduce homocysteine levels, however, its effect on cardiovascular morbidity and blood pressure is rather controversial. ...
... 11 Studies have documented that deficiencies of vitamin cofactors and inherited enzyme deficiency or mutation predispose to hyperhomocysteinaemia which has been shown to be associated with endothelial injury and consequently raised blood pressure. [11][12][14][15] It has also been reported that vitamin supplementation can reduce homocysteine levels, however, its effect on cardiovascular morbidity and blood pressure is rather controversial. [11][12][13][14][16][17][18][19][20][21] Hyperhomocysteinaemia has been classified into moderate (>15-30 µmol/L), intermediate (>30-100 µmol/L) and severe (>100 µmol/L) forms with normal levels between 5-15 µmol/L. ...
Background:
This study aimed at evaluating the prevalence of hyperhomocysteinaemia in Northern-Nigerian hypertensives and its association with hypertension severity and some major determinants as data regarding these are lacking in sub-Saharan Africa.
Method:
A Community-based cross-sectional study done on 120 randomly-selected hypertensive patients who responded to an ABU radio frequency modulated invitation for free health-screening at the Ahmadu Bello University (ABU) Medical Centre from January 2016 to June 2016. The percentage of participants with high homocysteine levels, their anthropometric parameters and blood pressures were determined. Plasma homocysteine (hcy) was classified as normal (5-15), moderate (>15-30), intermediate (31-100) and severe (>100) µmol/L. Kruskal-Wallis test was applied and log-transformed homocysteine (Ln10Homocysteine) was correlated with systolic and diastolic blood pressures as well as age, body mass index, fasting blood glucose, glomerular filtration rate, hypertension duration and Ln10folate in males and females using the Pearson's Correlation analysis.
Results:
There were 83(69.2%) females and 37(30.8%) males with Median homocysteine of 20.8 µmol/L and 22.0 µmol/L respectively (p=0.003). Hyperhomocysteinaemia was found in 118(98.3%) hypertensives while 2(1.7%) subjects had normo-homocysteinaemia. Moderate hyperhomocysteinaemia (Median, 20.8 µmol/L) was identified in 105(87.5%) and intermediate (Median, 40 µmol/L) in 13(10.8%) (p<0.001). No subject had severe hyperhomocysteinaemia. Homocysteine was higher (p=0.003) in subjects with Stage 2 systolic hypertension. Ln10Homocysteine was significantly (p<0.001) correlated with blood pressure (SBP: r=0.45; DBP: r=0.40) and age (r=0.33).
Conclusion:
The prevalence of hyperhomocysteinaemia in North-Western Nigerian hypertensives is high as against normal healthy controls. Plasma homocysteine is higher with severe systolic hypertension and positively associated with age.
Funding:
No specific grants but Micro Nova Pharmaceuticals Limited, Nigeria and Emzor Pharmaceutical Industries, Lagos, Nigeria supported with drugs.
... Inverse correlations between folate and Hcy have been observed [6,7]. An elevated concentration of total Hcy (tHcy), so-called hyperhomocysteinemia (HHcy) (>15 μmol/L, elevated range 10-15 μmol/L normal range < 10 μmol/L) [8], may be caused by various factors, including increasing age, male sex, ethnicity, genetic variations, end-stage renal disease, obesity, and hormonal factors, in addition to folate deficiency [9]. HHcy, a strong and independent risk factor for progressive cardiovascular disease (CVD), is associated with coronary artery disease (CAD), stroke, and age-related diseases in older people [4,[10][11][12][13][14]. Conventional risk factors, including age, sex, dyslipidemia, hypertension, diabetes mellitus (DM), and smoking are also significant risk factors for CVD [9,15,16]. ...
... An elevated concentration of total Hcy (tHcy), so-called hyperhomocysteinemia (HHcy) (>15 μmol/L, elevated range 10-15 μmol/L normal range < 10 μmol/L) [8], may be caused by various factors, including increasing age, male sex, ethnicity, genetic variations, end-stage renal disease, obesity, and hormonal factors, in addition to folate deficiency [9]. HHcy, a strong and independent risk factor for progressive cardiovascular disease (CVD), is associated with coronary artery disease (CAD), stroke, and age-related diseases in older people [4,[10][11][12][13][14]. Conventional risk factors, including age, sex, dyslipidemia, hypertension, diabetes mellitus (DM), and smoking are also significant risk factors for CVD [9,15,16]. Higher levels of Hcy found in patients with myocardial infarction positively correlated with low-density lipoprotein (LDL), but negatively with high-density lipoprotein (HDL) [17]. Lower serum LDL, higher serum HDL, and lower LDL/HDL ratio were reported to be associated with serum folate level [18]. ...
... Thus, our findings showed significant associations between increasing age, sex, Hcy, and risk factors for CVD in the elderly. Taking into account the previous studies [9,15], we conclude that high Hcy level, old age, male sex, and conventional risk factors for CVD, including hyperlipidemia, hypertension, and smoking, may create a high risk for cardiovascular events. ...
A lower serum folate level is common in older populations and is associated with increased serum homocysteine concentration. In turn, an elevated homocysteine level is associated with increased risk of cardiovascular disease and age-related diseases. Contemporary studies of folate and dietary risk factors for cardiovascular disease among the elderly population in Thailand are lacking. This cross-sectional study aimed to investigate the relationships among serum folate, homocysteine level, and nutritional status in the elderly Thai. Three hundred individuals, aged 60 years and over, underwent anthropometric and physiological measurements, and biochemical parameters, and eating habits were also determined. Folate insufficiency was found in approximately 35% of subjects. Folate and homocysteine showed a significant inverse correlation. Serum homocysteine levels rose with increasing age. Folate deficiency and high waist-to-hip ratio were associated with 7-fold and 2.5-fold increased risk for hyperhomocysteinemia, respectively. There were positive correlations between homocysteine and waist-to-hip ratio and systolic blood pressure, but a negative correlation between homocysteine and high-density lipoprotein (r = -0.239, p < 0.01), which are markers for cardiovascular disease risk. Folate negatively correlated with body mass index, waist-to-hip ratio, and diastolic blood pressure, but positively with high-density lipoprotein (r = 0.162, p < 0.01). Investigation of eating habits showed that low consumption of green leafy vegetables and high consumption of sugary foods were associated with high homocysteine levels. Given associations between nutritional status and cardiovascular disease confirmed in this study, nutrition education, holistic health promotion, and appropriate behavioral modification of eating habits represent important measures for preventing premature cardiovascular disease in the elderly Thai population.
... Many studies over the past 40 years have confirmed homocysteinemia as a strong risk factor for arterial and venous thromboembolism and for atherosclerotic vascular disease in the coronary, cerebral and peripheral vessels (Selhub, 1999;Nygård et al., 1999;Kalra, 2004;Wang et al., 2014;Cacciapuoti, 2011;Larsson et al., 2019;Abby et al., 1998;Marcus et al., 2007;Boers, 1997;D'Angelo et al., 1997;Maron and Loscalzo, 2006;Koller et al., 2018) -12, 2013;Smith et al., 2018), especially with regard to cardiovascular mortality . Moreover, homocysteine is suspected of having a carcinogenic effect (Kim et al., 2018). ...
... There may be several reasons for this observation. Firstly, numerous studies and International Consensus Statements from the past 40 years have confirmed that homocysteinemia is a risk factor for cardiovascular events and diseases (Selhub, 1999;Nygård et al., 1999;Kalra, 2004;Wang et al., 2014;Cacciapuoti, 2011;Larsson et al., 2019;Abby et al., 1998;Marcus et al., 2007;Boers, 1997;D'Angelo et al., 1997;Maron and Loscalzo, 2006). Already in 1998, Refsum et al. showed that elevated homocysteine levels are a strong predicting factor for cardiovascular mortality and Koller et al. implicated in 2018 that homocysteine itself causes endothelial damage (Koller et al., 2018). ...
Background
Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) are preclinical stages of Alzheimer's Disease (AD), which is the most common entity of dementia. Homocysteine is an amino acid in the methionine cycle, and many studies revealed a significant association between elevated homocysteine serum levels and the progression of dementia. The primary objective of this retrospective study was to investigate whether elevated homocysteine serum levels could be associated with mortality and neuropsychological test results in individuals suffering from SCD, MCI or AD.
Methods
This study is a single-center explorative retrospective data analysis with 976 data protocols from the Memory Outpatient's Clinic of the Medical University of Vienna included. All patients underwent a neurological examination, a laboratory blood test, and neuropsychological testing to establish a diagnosis of either SCD, MCI, or AD. Data was evaluated by Kaplan-Meier functions, factor analysis, and binary logistic regression models.
Results
Patients with AD showed significantly higher mean homocysteine levels (SCD 12.15 ± 4.71, MCI 12.80 ± 4.81, AD 15.0 ± 6.44 μmol/L) compared to those with SCD and MCI (p ≤ .001). The mean age of patients with AD (75.2 ± 7.8) was significantly older at the time of testing than of patients with MCI (69.1 ± 9.6) or SCD (66.8 ± 9.3). Since homocysteine levels increase with age, this could be a possible explanation for the higher levels of AD patients. The age at death did not differ significantly between all diagnostic subgroups, resulting in the shortest survival times for AD patients. Homocysteine levels were negatively associated with in Mini-Mental State Examination (MMSE) and Neuropsyhcological Test Battery Vienna (NTBV) factors F1-F4 (F1 = attention, F2 = memory, F3 = executive functions, F4 = naming/verbal comprehension). Moreover, higher homocysteine levels significantly predicted shorter five-year survival in the logistic regression models, even after adjusting for age, diagnostic subgroups, sex, years of education and results of neuropsychological testing.
Conclusion
The results of this study suggest that homocysteine levels are independently associated with impaired cognitive function and increased five-year mortality.
... The role of moderate hyperhomocysteinemia as an independent risk factor for CHD has been recently supported in many case-control studies (8) . Information on nutrition and health status of the Jordanian population is relatively scanty. ...
... Plasma tHcy levels increase with age and are higher among males than females. Due to the fact that age and gender differences are related to diet and vitamin status (8) , the contradiction in our findings cannot be explained in the absence of vitamin measures. ...
Objective: To examine the association between hyperhomocysteinemia and the risk of coronary heart disease and to highlight the relation between hyperhomocysteinemia and other risk factors of coronary heart disease including smoking, hypertension, and hypercholesterolemia. Methods: A total of 45 patients with coronary heart disease and 35 healthy controls of either sex, aged 60 years or less, were examined. Blood samples were obtained from all subjects at fasting and 4 hours after a methionine-loading test. The risk for hyperhomocysteinemia and its relation to other risk factors were examined by logistic regression analyses. Results: Sixty percent of the patients had hyperhomocysteinemia (fasting and postload) as compared to 40% of the controls. The odds ratio for coronary heart disease in patients with elevated fasting and postload homocysteine was 1.85 (C.I = 1.3-2.5, p=0.00) and 1.24 (C.I =1.1-1.39, p=0.00) respectively. No interaction between hyperhomocysteinemia and other conventional risk factors was observed. The likelihood of a coronary heart disease event increased approximately by 2-fold in patients with elevated fasting homocysteine levels, and by 1.24-fold in those with elevated postload homocysteine levels. Only smoking and hyperhomocysteinemia were strong predictors for coronary heart disease among our study group. Conclusion: Hyperhomocysteinemia is significantly and independently associated with coronary heart disease in our Jordanian sample.
... The choline oxidation pathway and its related metabolites have been linked to the development of cardiovascular disease (CVD), type 2 diabetes, cancer and all-cause mortality [1][2][3][4]. This pathway is part of a larger set of one-carbon metabolic processes including the methionine-homocysteine and folate cycles (Fig. 1). ...
Background
The choline oxidation pathway and metabolites involved have been linked to diseases including cardiovascular disease, type 2 diabetes and cancer. A healthy Nordic diet is a recently defined dietary pattern associated with decreased risk for these diseases. Our aim was to explore associations between adherence to a healthy Nordic diet and plasma concentrations of metabolites of the choline oxidation pathway.
Methods
The Healthy Nordic Food Index (HNFI) and Baltic Sea Diet Score (BSDS) were applied to cross-sectional data (n = 969) from the Västerbotten Intervention Programme in Northern Sweden to score adherence to a healthy Nordic diet. Data included responses to a dietary questionnaire and blood sample analyses (1991–2008). Associations of diet scores with plasma concentrations of metabolites of the choline oxidation pathway and total homocysteine (tHcy), seven metabolites in total, were evaluated with linear regression, adjusting for age, BMI, education and physical activity.
Results
HNFI scores showed linear relationships with plasma choline (β = 0.11), betaine (β = 0.46), serine (β = 0.98) and tHcy (β = − 0.38), and BSDS scores with betaine (β = 0.13) and tHcy (β = − 0.13); unstandardized beta coefficients, all significant at P < 0.05. The regression models predicted changes in plasma metabolite concentrations (± 1 SD changes in diet score) in the range of 1–5% for choline, betaine, serine and tHcy. No other statistically significant associations were observed.
Conclusions
A healthy Nordic diet was associated with plasma concentrations of several metabolites of the choline oxidation pathway. Although relationships were statistically significant, effect sizes were moderate. Further research is warranted to explore the underlying mechanisms and associations with health outcomes.
... In our cohort study, we also found that the increase of betaine intake was inversely correlated with the level of tHcy. Homocysteine had adverse effects on vascular endothelial cells and smooth muscle cells, further lead to inflammatory reaction and promoted the formation of atherosclerosis (53) . The increase of daily betaine intake can increase the concentration of SAM in plasma. ...
This study is design to explore the association between dietary betaine intake and risk of all-cause and cardiovascular death in patients with CAD. In this cohort study, 1292 patients with CAD were followed-up for a median of 9.2 years. Baseline dietary betaine intake was collected using a paper-based semi-quantitative food frequency questionnaire (FFQ) and assessed according to the US Department of Agriculture (USDA) Database and the data of betaine in common foods. Cox proportional hazards regression models were used to analyze the association between dietary betaine intake and risks of all-cause and cardiovascular mortality. During the follow-up periods, 259 deaths recorded in 1292 participants, of which 167 died of cardiovascular diseases. Patients in the highest tertile of dietary betaine intake had a lower risk of all-cause (P=0.007) and cardiovascular death (P<0.001) than those in the lowest tertile after adjusting for age and sex, traditional cardiovascular risk factors and other potential confounders. After further adjusting for plasma methionine metabolites and vitamins, HRs across tertiles of dietary betaine intake were 1.00, 0.84 and 0.72 for all-cause mortality (P for trend=0.124), and 1.00, 0.77 and 0.55 for cardiovascular mortality (P for trend=0.021). Higher dietary betaine intake was associated with a decreased risk of cardiovascular death after fully adjustment for cardiovascular risk factors, other potential confounders and plasma methionine metabolites and vitamins. However, the association between dietary betaine intake and risk of all-cause mortality was not statistically significant after further adjusting for plasma methionine metabolites and vitamins.
... Indeed, there is an inverse correlation between the concentration of folate and that of homocysteine in the blood (Jacques et al., 1999). Many clinical studies, beginning with the observations of children with homocystinuria presenting with vascular abnormalities and thromboembolism (McCully, 1969), have demonstrated an association between hyperhomocysteinemia and increased risk of premature atherosclerosis in the coronary, carotid, and peripheral vasculatures (Refsum et al., 1998). Even mild hyperhomocysteinemia is recognized to be an independent risk factor for cardiovascular disease. ...
Folate is a B vitamin consisting of multiple interconvertible chemical forms that are involved in cellular one-carbon metabolism, which is essential for purine and pyrimidine synthesis (for incorporation into DNA and RNA), amino acid interconversions, methylation reactions, and the generation and use of formate. The classical clinical manifestation of folate deficiency is megaloblastic anemia. Other consequences of folate deficiency include elevated plasma homocysteine or hyperhomocysteinemia (a risk factor for vascular disease), cancer initiation, neurological and cognitive impairment, depression, neural tube defects, and other negative birth outcomes. Fortification of cereal and grain food products with folic acid, the synthetic supplement form of folate, was first instituted in the US and Canada in the mid-to-late 1990s and has significantly reduced the incidence of neural tube defect affected pregnancies, as well as the overall prevalence of folate deficiency in the general population. Folic acid fortification, along with folic acid supplement use, may have additional influences on cancer rates, vascular disease, fetal and child development, and the severity of manifestations of vitamin B12 deficiency, though such effects are controversial and require further investigation.
... Since cobalamin absorption is often declined in the elderly, vitamin B12 deficiency is one of the most important nutritional problems in this population (2)(3)(4)(5). Recent studies suggest that inadequate vitamin B12 levels can promote the risk of atherosclerotic and neurodegenerative diseases (3,(6)(7)(8)(9). ...
Background: Vitamin B12 is a micronutrient essential for deoxyribonucleic acid (DNA) synthesis, which can affect osteogenesis. Based on in-vivo investigations, vitamin B12 is associated with osteogenesis, and low levels of this vital vitamin in the human body can be related to an increased risk of osteoporosis.
Methods: In this descriptive-analytical study, 60 women over 65 years who visited an orthopedic clinic were included. They were divided into three groups based on bone density in the hip and lumbar areas using dual-energy X-ray absorptiometry (DEXA) scans, including normal bone density, osteopenia, and osteoporosis. The average serum level of vitamin B12 in the experimental subjects was then determined and compared.
Results: 6 (10%) showed normal bone density, 25 (41.7%) osteopenia, and 29 (48.3%) were considered to have osteoporosis. Measured vitamin B12 levels showed no statistically significant difference between the two groups of normal bone density (601.3 ± 194.8) and osteopenia (560.4 ± 131.5). However, there was a significant statistical difference between vitamin B12 levels in people with osteoporosis (400.7 ± 162.4) and the two groups of normal and osteopenic individuals. There was also a negative statistical relationship between vitamin B12 levels and bone density (P = 0.004, r = -0.8).
Conclusion: A low serum level of vitamin B12 is associated with a severe decline in bone density in elderly Iranian women.
... In addition to inflammation, hyperhomocysteinemia may lead to atrial fibrillation in patients with celiac disease. Homocysteine is an amino acid produced during the metabolism of methionine (35). In diseases such as celiac disease that cause folate deficiency, homocysteine metabolism is impaired and hyperhomocysteinemia occurs. ...
... Finally, increased coffee consumption has been related to elevated homocysteine levels (Nygard et al 1998). ...
Mild hyperhomocysteinaemia occurs commonly in individuals in the general population and has been associated with increased risk of developing atherosclerosis and coronary artery disease. Mutations in the enzymes regulating homocysteine metabolism have been associated with elevated plasma homocysteine levels. There are three main enzymes involved in homocysteine metabolism; Methylenetetrahydrofolate reductase (MTHFR), that is involved in the remethylation pathway, Methionine synthase (MS) that is also involved in the remethylation pathway and Cystathionine beta synthase (CBS) that is involved in the transsulphuration pathway. Healthy middle aged men, from eight general practices across Britain (Northwick Park Heart Study II) were examined for plasma homocysteine levels and genotyped for the C677T polymorphism in the MTHFR gene, the 68 bp insertion polymorphism in exon 8 of the CBS gene and the A2756G polymorphism in the MS gene. Genotype at all three loci were associated with differences in plasma homocysteine level. Individuals homozygous for the MTHFR 677T allele had highest median homocysteine levels when compared to the other two genotypes (p<0.001). The raising effect associated with homozygosity for the 677T allele was greater in men in the lowest quartile of folate (interaction p=0.02). Furthermore there was an interaction between MTHFR and CBS genotypes and between MS and CBS genotypes. Age, folate, B12 and smoking explained 24.2% of the variance while the three genotypes combined and with interaction terms explained an additional 3.8%. This interaction between CBS genotype and MTHFR and MS genotypes points to a key role of the CBS transsulphuration pathway in the metabolism of homocysteine that may be particularly important in subjects with low dietary folate. Elderly men and women from two towns, of contrasting risk of developing of coronary artery disease, Dewsbury and Maidstone, were examined for plasma homocysteine levels and genotyped for the C677T and the A1298C polymorphisms in the MTHFR gene. Plasma homocysteine levels were significantly higher in men from the coronary artery disease high risk town of Dewsbury than in the low coronary artery disease risk town of Maidstone (p<0.001), but not in women. Women in both towns had significantly lower plasma homocysteine than men. There was no difference between towns in plasma folate or B12 levels but the conventional inverse relationship with plasma homocysteine was seen. There was a significantly higher number of males homozygous for the 677T allele in Dewsbury than in Maidstone; 12.8 % vs. 6.7% respectively (p=0.05). Similar frequency difference for homozygosity were seen for women; 13.3% vs. 8.0% (p=0.05) suggesting a true regional frequency difference. The regional differences in plasma homocysteine levels were still present after the adjustment for folate levels, B12 levels, smoking and the effect of the C677T polymorphism. These observations may have a bearing on regional differences in plasma homocysteine levels and the variation in coronary artery disease risk between regions in the UK. The degree of reduction of homocysteine levels after administration of folic acid from different sources was examined in relation to common polymorphisms that have been identified in the MTHFR gene. Fifty-nine subjects from New Zealand received similar doses of folic acid in different forms, i.e. synthetic supplements, fortified cereals and fruits. The most effective way to lower homocysteine levels was through administration of synthetic supplements of folate. The genotype response to folate administration was examined and it was concluded that individuals with the thermolabile variant have a more profound response than any of the other genotypes after folate administration for 12 weeks. However, the homocysteine levels at the end of the intervention period were very similar between groups that received the same folate treatment irrespective of genotype.
... In the transsulfuration pathway, Hcy is converted to cystathionine by cystathionine β-synthase (CBS) and finally to cysteine using vitamin B6 as a co-factor. 10 HHC is due to several factors such as age and gender, genetic disorders linked to enzymatic deficiencies, ethnicity, life-style factors, poor vitamin intake, liver, renal or thyroid disease, comorbidities, and drug use, 11,12 and differences in the definitions of HHC. 13,14 Although establishing the true frequency of HHC is an almost impossible task because of the number of variables described in association with this phenomenon, more information about this metabolic abnormality and its frequency is given in the literature. ...
Background
Hyperhomocysteinemia, a thrombotic risk factor, may have several causes. Among the genetic causes of hyperhomocysteinemia, there are polymorphisms in the enzymes methylenetetrahydrofolate reductase (C677T) and cystathionine β-synthase (C699T, C1080T, and 844ins68). Although the frequency of hyperhomocysteinemia in our country is high, there is no evidence about the frequencies of these polymorphisms.
Methods
We analyzed 80 healthy individuals from several regions in our country. We evaluated the fasting and post-oral methionine load plasma Hcy and the genotypes in order to obtain the allele frequencies of the polymorphisms C677T of methylenetetrahydrofolate reductase and C699T, C1080T, and 844ins68 of the cystathionine β-synthase.
Results
No individual had deficiency of folic acid, vitamins B12, or B6, but 80% had post-oral methionine load hyperhomocysteinemia. We found a significant increase in the Hcy plasma concentration associated with age and gender. Only the polymorphism C1080T was significantly associated with hyperhomocysteinemia.
Conclusion
There is an association between fasting and post-oral methionine load plasma Hcy concentrations with the allelic frequencies of the polymorphisms C669T, 844ins68, and C1080T of the cystathionine β-synthase and C667T of the methylenetetrahydrofolate reductase in healthy Mexican individuals. As compared with individuals with normal fasting or post-oral methionine load Hcy plasma levels, only C1080T was significantly associated with hyperhomocysteinemia.
... Homocysteine is recognised as an independent risk factor for atherosclerotic vascular disease and for venous thrombosis (Refsum at al, 1998). As much as 1 0 % of all cardiovascular risk may be attributable to high levels of homocysteine (Boushey at al, 1995). ...
Oxidative stress has been implicated in the pathogenesis of various diseases including cancer, septic shock, stroke, hypertension and atherosclerosis. This manifests itself in oxidative modification of low-density lipoprotein (LDL) and the expression of specific proteins such as tissue factor (TF). It has been claimed that some of these effects can be reversed by dietary antioxidants and that at least some of these actions may be at gene level in vascular cells. The aim of the project was to study the effects of minimally oxidised low-density lipoprotein (mmLDL) and the bacterial endotoxin - lipopolysaccharide (LPS) on the expression of genes for TF and TF pathway inhibitor (TFPI) in a human monocytic cell line (THP-1) and the cell line ECV 304 (once thought to be of endothelial origin). The effect of antioxidant vitamins on the expression of these genes was elucidated. The action of the antioxidant vitamins on TF protein activity was also investigated. The principal antioxidants studied were ascorbate, α-tocopherol and lutein. The mode of action of the antioxidants was also studied through the involvement of selected nuclear transcription factors (NFkB, CREB, ELK-1 and HIF-1). In this study, Quantitative Competitive RT-PCR (QC RT-PCR) was successfully developed and applied for the determination of the changes in TF and TFPI expression. Some of the results were confirmed using Northern blot techniques. There was simultaneous expression of TF and TFPI mRNA in both THP-1 and ECV 304 cells after stimulation with a range of effectors. When an increase in TF expression was evident, a corresponding decrease in TFPI expression was noted in the case of LPS stimulation. The study confirmed that mmLDL and LPS are potent inducers of TF expression in THP-1 and ECV 304 cells. The treatment of cells with antioxidant vitamins significantly suppressed the induction of the TF gene and also induced the expression of TFPI mRNA. LPS and mmLDL also increased TF pro-coagulant activity on the surface of the cells and this activity was suppressed by antioxidants. Also, the antioxidants have effects on some of the nuclear transcription factors studied. The timing of the effects of antioxidants was given particular attention.
... 4 Stipulated theories include abnormal trophoblastic invasion of uterine vessels, discordance of immunologic tolerance between placental and fetal tissues, genetic and dietary factors. 5 As evident from vast medical literature, homocysteine, a sulfur containing amino acid has been implicated in the causal pathway of these hypertensive disorders of pregnancy. Normally, as pregnancy progresses, serum homocysteine falls due to hemodilution, increase in estrogen and increased demand for methionine by both mother and fetus. ...
... Among the acquired biological risk factors, the presence of lupus anticoagulant has also led to the interpretation of a number of thromboses. Recently, the role of Hcys in thrombotic pathology has often been cited to explain cases of unconventional thrombosis [24,25,26]. One study showed significantly higher rates in patients under 60 years of age with venous or arterial thrombosis compared to controls, a difference that was especially marked in women between 30-44 years old. ...
... It is produced during the enzymatic demethylation of methionine, an essential amino acid [1,2]. At present, high plasma homocysteine level is regarded a primary and independent risk factor in the etiopathogenesis of coronary heart disease and cerebrovascular diseases [3][4][5][6]. ...
INTRODUCTION: It is claimed in a limited number of studies carried out on human beings that plasma homocysteine levels increased in hypothyroid patients and decreased in hyperthyroid patients. OBJECTIVE: The aim of this study is to determine total plasma homocysteine, thyroid function tests, vitamin B12, folic acid and lipid levels and to explore the relations among them in rat models with induced hypothyroidism and hyperthy-roidism with a view to investigating whether hypothyroid and hyperthyroid rat models could represent human hypothyroidism and hyperthyroidism models. MATERIAL AND METHOD: The study included 30 male Wistar Albino species rats with a mean weight of 200-250 g. Rats were randomly divided into 3 groups as 1) hypothyroid group, 2) hyperthyroid group and 3) control group. Hypothyroidism was induced by adding 10 mg/kg/day propylthiouracil to rats' drinking water for 30 days. In order to induce hyperthyroidism, rats were administered 10 µg/100 g L-thyroxin ampule via intraperitoneal route for 10 days. RESULTS: We found that total plasma homocysteine level of the hypothyroid group was significantly lower than those of the control group (p<0.05) and the hyperthy-roid group (p<0.001). Total plasma homocysteine level of the hypothyroid group was found insignificantly higher than that of the control group (p>0.05) and significantly higher than that of the hyperthyroid group (p<0.001). We established a significant and positive correlation between total plasma homocysteine level and thyroid hormone levels. We did not identify a significant relation between total plasma homocysteine level and serum folic acid and serum vitamin B12 levels. CONCLUSION: Our findings are different from the findings reported in human hypothyroidism and hyperthyroidism studies. We believe that hypothyroid and hyperthyroid rat models cannot represent human hypothyroidism and hyperthy-roidism models.
... Homocysteine concentration is higher in men than women and increases with age.The difference becomes apparent in puberty and it is related to hormonal factors, lifestyle, nutrition, and vitamins. Thromboembolic events were present in 50% of untreated persons with high level of homocysteine, and 20% die before the age of 30 years (Nygård et al., 1999). Numerous clinical studies demonstrated a relationship between total homocysteine levels and CAD, LEAD, stroke or venous thrombosis (Boushey et al., 1995;Verhoef & Stampfer, 1995).The homocysteine affects the coagulation system and the resistance of the endothelium to thrombosis and may interfere with the vasodilator and antithrombotic effects of nitric oxide (Stamler & Slivka, 1996). ...
Introduction: Arab Middle East Countries which have a predominance of young population have undergone rapid socioeconomic changes, instability and epidemiologic transition. In these countries cardiovascular disease (CVD) mortality accounts for 45% of deaths, in Palestine it was estimated up to 30.3% in 2018. Also, the burden of risk factors is worrying; one quarter of adult population was hypertensives, tobacco smoking exceeds 30% in males, obesity is alarming mainly in females, and 9.2% of adults are living with diabetes. Very few community-based on CVD studies were conducted in these countries. Methods: In 2017 a cross-sectional study using stratified cluster sample, was conducted in accordance with WHO’s STEP wise. A sample of 2240 participants aged ≥25 years participated in the study. Results: The prevalence of CAD is 8.3%, stroke 3.0%, hypertension is found with a prevalence of 28.4%, diabetes19.1% and obesity 47.8% with higher rate in females (60%). Lower extremity artery disease (LEAD) is found with a prevalence of 13.7%. The prevalence increased with age and is higher in females than in males (respectively15.6% vs 11.6%). Hypertension and diabetes are the most significant associated factors with LEAD. Metabolic syndrome is present with a prevalence of 41% higher in females than males (50% vs 39%) and it is significantly associated with all cardiovascular conditions. Conclusion: According to these data the situation in Gaza strip is alarming, effort and research to monitor and improve strategies and policies for reducing cardiovascular risk are mandatory
... While slight age-related increases are considered physiological, the high Hcy levels observed at younger ages are linked to genetic predisposition and environmental factors (smoking, toxic carcinogenic substances and drugs) (Corrales et al., 2002;Carmel and Jacobsen, 2001;Refsum 1998;Wijekoon et al., 2006;Varga 2005;Richards 2008;Hankey and Eikelboom 1999;Graham et al., 1997;Martinez et al. 2017;Ramakrishnan et al., 2006;Piccione et al., 2008). An increase in the homocysteine level is an indicator of lower intake of foods containing vitamin B12, or malfunction of renal functions or possibly a low enzyme activity in the metabolism of homocysteine (Martinez et al., 2017;Furlong et al., 2010;Murin et al., 2017). ...
... The correlation between Hcy and cardiovascular diseases has been known since the 1960s [6]. A disturbance in the Hcy metabolic pathway causes Hcy accumulation leading to Hyperhomocysteinemia (Hhcy) [7][8][9]. In addition, common causes for Hhcy are: renal disease [10], insufficiency of vitamins contributing to Hcy metabolism [11], excess amount of dietary methionine [12][13] and also deficit of enzymes involved in Hcy metabolism [3]. ...
Homocysteine (Hcy) is a critical indicator of cardiovascular disease. High levels of Hcy have now been recognised as a risk factor for the development of a wide range of diseases. Hyperhomocysteinemia (Hhcy) can be induced by methionine or Hcy supplementation. On the other hand, Glutathione (GSH) is a major antioxidant in the body and also an important compound for oxidative defence. It is composed of 3 amino acids: cysteine, glutamate, and glycine. Interestingly, methionine is also a crucial compound in GSH synthesis. This study aims to assess the impact of 1% L-methionine feeding (10 or 30 weeks) on the body weight and serum Hcy and GSH levels of young adult (16 weeks) and middle-aged (36 weeks) Wistar rats of both sexes. Serum was analysed for Hcy and reduced GSH levels by liquid chromatography mass spectrometry (LCMS) in response to 1% L-methionine feeding. One percent L-methionine feeding decreased body weight in all conditions investigated, although this only reached significance in males after 10 weeks supplementation and females after 30 weeks supplementation. It also induced a significant increase in the serum Hcy levels of male Wistar rats, whilst having no significant effect on Hcy serum levels in female rats. Finally, we also observed a small increase in serum GSH levels in female Wistar rats but no change in serum GSH levels in the males. These results suggest that methionine feeding affects body weight homeostasis and alters by products of methionine catabolism.
... 2 Homocysteine is a sulfur-containing essential amino acid primarily derived from demethylation of dietary methionine required for the growth of cells and tissues in the human body. 3 The normal range of serum homocysteine was taken as 5-15 µmol/L. ...
... Homocysteine is a non-protein forming sulfurcontaining amino acid, formed as a primary intermediate during the metabolism of methionine, and Hcy is extremely important for optimal cellular function and survival (33) . The enzyme cystathionineβ-synthase and methylene tetrahydrofolate reductase (MTHFR) together with cofactor folic acid, vitamin B6 and vitamin B12, play a key role in the regulation of circulating homocysteine levels, hence a genetic defect in one of the enzymes or the cofactor of homocysteine metabolism can lead to metabolic disruption and potentially to Hyperhomocysteinemia (34). ...
Background Polycystic ovary syndrome (PCOS) a complex endocrine disorder associated with reproductive disorders and metabolic dysfunctions, insulin resistance with compensatory hyperinsulinemia, obesity, endometrial carcinoma, and cardiovascular diseases. Objectives This study aims to evaluate the levels of IL-18 and homocysteine in serum as a possible biomarker for cardiovascular disease in 150 cases positive with PCOS and in 150 negative control females. Patients and Method This study was a case-control study and serum samples randomly taken from 300 individuals (150 samples from patients with PCOS and 150 samples from healthy controls). Five milliliters of venous blood has been taken from each individual and the samples were analyzed for interleukin-18 and homocysteine by using enzyme-linked immunosorbent assay, hormones profile include LH, FSH, LH/FSH ratio, TSH, PRL, and Testosterone. Results We found that the average level of IL-18 and homocysteine in serum were 378.3 ±181.21 pg/ml and 10.36 ± 5.98 nmol/ml respectively in PCOS patients, while in the control group the values were 224.98± 131.885 pg/ml and 5.17± 5.24 nmol/ml respectively. Conclusions The results show a highly significant difference (p-value < 0.001) and high serum concentration of IL-18 and homocysteine in PCOS as compared to the control group. Therefore, elevation of IL-18 combined with homocysteine is a selective indicator for higher risk of PCOS, which is closely related to cardiovascular abnormality as we have gated for this category of PCOS patients.
... Meynadier and Gilhou reported reduced folate levels in psoriasis results from its excessive consumption by the skin [13] . Some earlier studies indicates that Refsum et al., 1989, found that psoriasis patients had low serum folate and high HCY levels than age-matched controls [14] . Tobin AM and Brazelli reported increased HCy levels in patients with psoriasis. ...
... By decreasing vascular flexibility and impairing diastolic function of vessels, homocysteine shows atherogenic properties. This is confirmed through ultrasound examination, in which the degree of atherosclerosis in blood vessels is correlated with homocysteine concentration in blood samples of patients [49]. Moreover, this amino acid directly reacts with nitric oxide to give S-nitrohomocysteine, which also reduces the concentration of free nitric oxide. ...
For their being considered safe and as over-the-counter (OTC) drugs, proton pump inhibitors (PPI) are one of the most frequently used medicines nowadays. However, for the last couple of years, many researches analyzing PPI were conducted and these studies shed light on PPI side effects and mechanisms of these processes. Particularly, interesting is the impact of PPI on hearing loss development. However, this side effect seems to be local and its mechanisms are complex and systemic and involve changes in the whole body. This paper summarizes how through, inter alia, alterations in circulatory system, respiratory system, central nervous system, and metabolic changes PPI can cause hearing impairment, which can occur at every age and is connected with long-term use of this group of drugs. Another important finding is the role of PPI in acceleration of presbycusis development which is disturbing with regard to the fact that elders are the group who most frequently use PPI in the long term. Hearing loss is the factor which gravely decreases life quality, especially among elders who are the most afflicted group; thus, administration of PPI should be considered carefully, taking under consideration all benefits and all potential side effects.
... Hcy impairs endothelial function and leads to platelet activation and thrombus formation (Hanratty et al. 1998). Experimental evidence has demonstrated that elevated blood Hcy levels were significantly associated with an increased risk of cardiovascular events, which appears to be largely independent of other conventional risk factors (Refsum et al. 1998;Nygård et al. 1999). ...
The common variants of the methylenetetrahydrofolate reductase (MTHFR) gene are related to the activity of the MTHFR enzyme and the concentrations of blood homocysteine (Hcy). This study was designed to investigate the associations of MTHFR in Chinese populations with early-onset coronary artery disease (EOCAD). The two common variants of the MTHFR gene were genotyped in 875 EOCAD patients and 956 controls using PCR, followed by direct sequencing of the PCR product. Serum levels of Hcy were measured using an automatic biochemistry analyzer. A significant association between the MTHFR-677C/T variant and the risk of EOCAD was detected in CC versus TT (odds ratio (OR) 1.456, 95% confidence interval (CI) 1.120-1.892), dominant genetic model (OR 1.266, 95% CI 1.027-1.546), and recessive genetic model (OR 1.306, 95% CI 1.040-1.639). Hcy was most abundant in TT genotype (18.31 ± 7.22 μmol/L), least abundant in CC genotype (11.37 ± 5.23 μmol/L), and detectable at intermediate levels in heterozygotes (15.25 ± 6.58 μmol/L). Elevated serum Hcy levels were an independent risk factor for EOCAD (ORadjust 1.431, 95% CI 1.135-1.763). Our findings indicated that the T allele of -677C/T MTHFR variant predisposes to high levels of Hcy, and that the T allele is an important risk factor for EOCAD in the Chinese population.
... 7 Theories include abnormal trophoblastic invasion of uterine vessels, discordance of immunologic tolerance between placental and fetal tissues, genetic and dietary factors. 8 The cause behind cerebral irritation leading to convulsion in pre-eclampsia is not clear. The irritation is postulated to be provoked by anoxia, cerebral edema and cerebral dysrhythmia. ...
Background: Hypertensive disorders of pregnancy are a major cause of both maternal and foetal morbidity and mortality. Although pregnancy induced hypertension (PIH) is still regarded as a disease of theories and unknown etiology, elevated homocysteine level has been hypothesized as a key risk factor. Abnormally raised homocysteine has been significantly associated with increased risk of PIH, abruption, intrauterine growth restriction, recurrent pregnancy loss, intrauterine death and prematurity. Methods: The present case control study was conducted among 180 pregnant women (90 cases and 90 controls) in Kamla Nehru State Hospital for Mother and Child, IGMC Shimla, Himachal Pradesh with an objective of ascertaining the role of homocysteine in pregnancy related hypertensive disorders. Socio-demographic, clinical, biochemical including homocysteine level, laboratory and ultrasonographic parameters of all the participants were documented. Results: The mean homocysteine level of cases (18.30±10.81) was significantly higher than the controls (8.70±2.64). About 62.2% cases had abnormally raised homocysteine level (>15 μmol/L), while only 1.1% controls had such level. The odds of a case having abnormally elevated homocysteine level were 146.6 (CI: 19.52-1101) times to that of controls. Eclamptics had the highest homocysteine level followed by preeclamptics and controls. Conclusions: The present study significantly associates the abnormally elevated homocysteine levels with pregnancy related hypertensive ailments and demands much needed robustly designed studies to further explore the phenomenon. A simple intervention like estimating the much neglected homocysteine levels prior to pregnancy can definitely aid in predicting and preventing perinatal outcomes.
Keywords Abnormal homocysteine, Case control study, Eclampsia, Hypertensive disorders of pregnancy, Pre-eclampsia, Tertiary care institution
... The concept of homocysteine causing atherosclerosis was introduced by Mccully in 1999. Homocysteine is known to cause endothelial dysfunction leading to increased risk of thrombosis and cytotoxic effect on endothelium [14]. There could be another mechanism, DNA hypomethylation, by which homocysteine can cause atherogenesis [15]. ...
... Homocysteine levels on an average are below 10 µmol/L. Hyperhomocysteinemia can be moderate type, intermediate type, and severe type depending on the level of serum homocysteine: Moderate (15 to 30 µmol/L), Intermediate (30 to 100 µmol/L), Severe (greater than 100 µmol/L). 1 Causes of high serum homocysteine levels can be genetic factors determinants, lifestyle (vegetarian diet, high coffee consumption), medicines (methotrexate), etc. [2][3][4][5] Inadequate levels folate or of the B vitamins account for very high number of cases of hyperhomocysteinemia. 6 McCully and Wilson proposed the theory of high serum homocysteine levels leading to arteriosclerosis. 7 Research relating high homocysteine levels with vascular disorders has been done extensively in the last 10 to 15 years. ...
... available to date is that the incidence of congenital hypothyroidism in DS cases is definitely 30-fold higher than that of the general population. There are consistent reports demonstrating thyroid status as an important determinant of the plasma/serum concentration of tHcy [27,28,29] which has been proposed as an independent risk factor for vascular occlusive disease [30]. ...
Down's syndrome (DS) has lately been gaining attention among researchers due to its genetic significance leading to dementia and Alzheimer's disease. The aim of the present study was to investigate the possible interaction between thyroid hormone and total homocysteine levels by analyzing the patterns of chromosomal abnormalities and genetic polymorphisms of the methionine synthase reductase (MTRR) gene among DS children, mothers of DS children (MDS) and their respective controls. Free trisomy was present in 57%, translocation in 10% and mosaicism in 33% of DS children from mothers with abnormal thyroid hormonal and homocysteine levels. A combination of the heterozygous and homozygous MTRR variant (AG+GG) showed a highly significant increase in the prevalence of the A66G mutation among MDS. The prevalence of the GG homozygous variant was significantly higher in MDS compared to controls. Although the confinement of this study to a specific geographic region of India and the relatively small sample size, our observations support the integration of genetic analysis and biochemical tests for a potential prognosis of DS that could enable the implementation of prophylactic treatments.
... The differences observed between the results may be attributed to the period of the plant growth cycle, variety, cultivar conditions, weather and finally to the processing and preparation because leaves used by Monagas et al. (2006) were cultivated using the commercial dietary technology. Homocystein (Hyc) is considered as a risk marker and can be used for screening patients of high menace for cardiovascular events (Refsum et al., 1998). In this study, the oral administration of high dose of L-methionine 1 g/kg/day during 15 days showed a significant increase in the level of plasma tHyc compared to the control group. ...
This study was designed to detect the anti-oxidant and anti-inflammatory effects of phenolic compounds in grape leaves Algerian variety (GLAV) on endothelial damage. The phenolics were identified by using HPLC/DAD/ESI-MS analysis. The research of the anti-oxidant and anti-inflammatory effects was conducted on mice through 15 days. Results showed high levels of phenols, anthocyanins, flavonols and trans-caftaric acid in GLAV. The plasma hs-CRP and homocysteine levels were elevated significantly (p < 0.05) however the glutathione reduced significantly (p < 0.05) after the administration of L-methionine in high doses to mice. This was associated with the desquamation of endothelium and muscular lysis with transformation of spindle nuclei to oval nuclei; this is due to the angiotoxic action of homocysteine on the aorta. These changes were not observed in mice treated with L-methionine plus the antioxidant and anti-inflammatory extract of GLAV. So, the study proved the antioxidant and anti- inflammatory effects of the GLAV on hyperhomocysteinemia induced inflammatory endothelial damage in cardiovascular diseases.
... It improves heart health by reducing the level of Hcy in human body. High level of this amino acid is considered the main cause of heart attack (Refsum et al. 1998). Folate is also important for fertility in humans. ...
One sixth of the world’s population is suffering from hidden hunger that
indicates a gross malnutrition particularly among children and women of
third world countries. The deficiency of micro nutrients, especially iron (Fe)
causes a number of ailments such as megaloblastic anemia and neural tube
defects in poor population. There is a dire need to supplement iron in the
diet. Current efforts implicate fortification of wheat flour and other grains
with different iron formulations such as ethylenediaminetetraacetic acid
(EDTA), FeSO4 and elemental iron. However, all such interventions are not
sustainable due to logistic and quality assurance problems in resource-limited
settings. For a long term solution, development of crop plants with increased
micronutrients and iron bioavailability is essential. Therefore, biofortification
of cereal grains using translational genomics approaches for enhancement of
folate through genome editing in cereals is inevitable to mitigate the folate
deficiency in poor remote population in a cost effective manner.
... SAH-hydrolase (also known as adenosylhomocysteinase) hydrolyzes SAH in vivo when the products of this reaction, adenosine and HCyst, are rapidly removed. HCyst is a toxic by-product of sulfur amino acid metabolism and it is also known as an independent risk factor for cardiovascular diseases (8). MTHR (also called methionine synthetase), generates methionine by remethylating HCyst. ...
ถึงแม้ความเจริญก้าวหน้าทางการแพทย์ จะพัฒนาไปอย่างไม่หยุดยั้ง โรคหัวใจและหลอดเลือด (cardiovascular diseases) ยังคงเป็นสาเหตุการตายอันดับหนึ่งอยู่ทั้งในประเทศแถบซีกโลกตะวันตกเช่น สหรัฐอเมริกา แคนาดา อังกฤษ เป็นต้น นอกจากนั้นยังพบว่าประเทศแถบเอเชียเช่น จีน ญี่ปุ่น เกาหลี สิงคโปร์ ฟิลิปปินส์ รวมทั้งประเทศไทยเองก็ประสบปัญหาเดียวกัน ปัจจัยเสี่ยงที่ก่อให้เกิดโรคหัวใจและหลอดเลือด อันเป็นที่รู้จักกันดีในอดีตสามารถแบ่งออกได้เป็น 2 กลุ่มใหญ่คือ ปัจจัยที่เปลี่ยนแปลงได้ (modifiable risk factors) เช่นการสูบบุหรี่ ภาวะไขมันในเลือดสูง ความดันสูง เบาหวาน โรคอ้วน การไม่ออกกำลังกาย และปัจจัยที่เปลี่ยนแปลงไม่ได้(non-modifiable risk factors) คือ อายุ เพศ และประวัติโรคหัวใจและหลอดเลือดในครอบครัว ไม่สามารถอธิบายพยาธิสรีรวิทยาของการเกิดโรคหัวใจและหลอดเลือดในผู้ป่วยได้ทุกรายโดยพบว่าผู้ป่วยโรคหัวใจ และหลอดเลือดอีกเกือบ40เปอร์เซ็นต์ตรวจไม่พบปัจจัยเสี่ยงดังกล่าวทำให้นักวิจัยทั่วโลกพยายามค้นหาปัจจัยเสี่ยงใหม่ (new risk factors) ที่มีส่วนในการเกิดโรคหัวใจและหลอดเลือด โฮโมซีสทีนเป็นหนึ่งในปัจจัยเสี่ยงใหม่ที่นักวิจัยให้ความสนใจมากเป็นพิเศษ ร่วมกับทฤษฎีของพยาธิแพทย์ชาวอเมริกันคือ Kilmer S. McCully ผู้ค้นพบความจริงที่ว่าการเพิ่มสูงขึ้นของโฮโมซีสทีนในเลือดของเด็กที่ป่วยเป็นโรคทางพันธุกรรม homocystinuria ส่งผลทำให้เกิดภาวะหลอดเลือดแดงแข็ง (atherosclerosis) ก่อนเวลาอันควร โดย Kilmer S. McCully รายงานการค้นพบดังกล่าวไว้ตั้งแต่ปี ค.ศ.1969 หลังจากนั้นมีนักวิจัยให้ความสนใจในเรื่องดังกล่าวน้อยมากเนื่องจากคิดว่า homocystinuria เป็นโรคทางพันธุกรรมที่พบได้ยากและพบแต่ในเด็กเล็กๆเท่านั้นไม่น่าจะมีความสำคัญอะไรกับการเกิดโรคหัวใจและหลอดเลือดในผู้ใหญ่ จวบจนกระทั่ง 10 กว่าปีมานี้ มีนักวิทยาศาสตร์เป็นจำนวนมาก ที่หันมาให้ความสนใจค้นคว้าความสัมพันธ์ระหว่างโฮโมซีสทีนและภาวะหลอดเลือดแดงแข็ง โดยพบว่าโฮโมซีสทีนที่สูงขึ้นในเลือดในระดับที่ไม่สูงมากนัก ก็สามารถทำลายผนังด้านในของหลอดเลือดแดงและนำไปสู่ภาวะหลอดเลือดแดงแข็งก่อนเวลาอันควร จนกลายเป็นโรคหัวใจขาดเลือด กล้ามเนื้อหัวใจตาย และเสียชีวิตในที่สุด นอกเหนือจากนั้นยังพบว่า วิธีการแก้ไข และรักษาผู้ป่วยที่มีระดับโฮโมซีสทีนในเลือดสูงสามารถทำได้โดยง่ายด้วยการรับประทานวิตามินบี 6 วิตามินบี 12 และกรดโฟลิกให้เพียงพอ ก็สามารถทำให้ระดับโฮโมซีสทีนในเลือดลดลงได้ยกเว้นบางรายที่มีความผิดปกติทางพันธุกรรม ซึ่งไม่สามารถแก้ไขด้วยการให้วิตามินรับประทาน อย่างไรก็ตามแม้ว่าผู้ป่วยที่มีความผิดปกติทางพันธุกรรมจะไม่สามารถทำให้โฮโมซีสทีนในเลือดลดลงสู่ระดับปกติแต่ก็สามารถลดลงได้พอสมควรเข้าทำ-นองผ่อนหนักให้เป็นเบาได้ ผู้เขียนเล็งเห็นถึงความสำคัญดังกล่าวของโฮโมซีสทีนประกอบกับในประเทศไทยมีผู้ให้ความสนใจในเรื่องนี้น้อยมาก ทั้งๆที่อัตราการตายจากโรคหัวใจและหลอดเลือดของประเทศไทย ติดอันดับหนึ่งเช่นเดียวกับประเทศทางซีกโลกตะวันตก ผู้เขียนหวังเป็นอย่างยิ่งว่าความรู้ดังกล่าวจะก่อให้เกิดประโยชน์กับสังคมไทยโดยรวม และทำให้ประชาชนไทยมีสุขภาพที่แข็งแรงสมบูรณ์ขึ้น จากความร่วมมือร่วมใจ ของบุคลากรทางการแพทย์ทุกๆสาขาอย่างดียิ่ง
Creatine stores high-energy phosphate bonds in muscle and is synthesized in the liver through methylation of guanidinoacetic acid (GAA). Supplementation of GAA may therefore increase methyl group requirements, and this may affect methyl group utilization. Our experiment evaluated the metabolic responses of growing cattle to postruminal supplementation of GAA, in a model where methionine (Met) was deficient, with and without Met supplementation. Seven ruminally cannulated Holstein steers (161 kg initial body weight [BW]) were limit-fed a soybean hull-based diet (2.7 kg/d dry matter) and received continuous abomasal infusions of an essential amino acid (AA) mixture devoid of Met to ensure that no AA besides Met limited animal performance. To provide energy without increasing the microbial protein supply, all steers received ruminal infusions of 200 g/d acetic acid, 200 g/d propionic acid, and 50 g/d butyric acid, as well as abomasal infusions of 300 g/d glucose. Treatments, provided abomasally, were arranged as a 2 × 3 factorial in a split-plot design, and included 0 or 6 g/d of l-Met and 0, 7.5, and 15 g/d of GAA. The experiment included six 10-d periods. Whole body Met flux was measured using continuous jugular infusion of 1-13C-l-Met and methyl-2H3-l-Met. Nitrogen retention was elevated by Met supplementation (P < 0.01). Supplementation with GAA tended to increase N retention when it was supplemented along with Met, but not when it was supplemented without Met. Supplementing GAA linearly increased plasma concentrations of GAA and creatine (P < 0.001), but treatments did not affect urinary excretion of GAA, creatine, or creatinine. Supplementation with Met decreased plasma homocysteine (P < 0.01). Supplementation of GAA tended (P = 0.10) to increase plasma homocysteine when no Met was supplemented, but not when 6 g/d Met was provided. Protein synthesis and protein degradation were both increased by GAA supplementation when no Met was supplemented, but decreased by GAA supplementation when 6 g/d Met were provided. Loss of Met through transsulfuration was increased by Met supplementation, whereas synthesis of Met from remethylation of homocysteine was decreased by Met supplementation. No differences in transmethylation, transsulfuration, or remethylation reactions were observed in response to GAA supplementation. The administration of GAA, when methyl groups are not limiting, has the potential to improve lean tissue deposition and cattle growth.
Obesity is associated with changes in amino acid metabolism, and studies show that ingestion of fish proteins influence amino acid composition in plasma and urine, in addition to affecting risk factors for metabolic syndrome. Since the majority of fish proteins consumed by humans are as fish fillet, it is of interest to investigate if cod fillet intake affects amino acid composition and metabolic disorders. We hypothesized that a modified AIN-93G diet containing cod fillet would affect amino acid compositions in plasma and urine in obese rats, and also affect risk factors for metabolic syndrome when compared to rats fed a regular AIN-93G diet with casein as the protein source. Obese Zucker fa/fa rats, a rat model of metabolic syndrome, received diets containing 25% protein from lyophilized baked cod fillet and 75% protein from casein (Baked cod diet), or a Control diet with casein for four weeks. The Baked cod diet affected the amino acid composition in plasma, with e.g. lower glycine, histidine, homoarginine, homocysteine, methionine, proline and tyrosine concentrations, but did not affect amino acid concentrations in urine. The concentrations of markers for kidney dysfunction were lower in the Baked cod group, however blood pressure development, fasting and postprandial glucose, as well as hepatic triacylglycerol concentrations were similar to the Control group. To conclude, substituting 25% of dietary protein with baked cod fillet affected concentrations of some amino acids in plasma and delayed development of kidney and liver dysfunction, but did not affect blood pressure, glucose concentration or fatty liver.
Inflammation is a natural clinical repair response of body’s immune system to protect its tissues from various noxious stimuli that continues to remodel throughout the lifecycle because of interactions between genes, lifestyles, and environments. There is a link between inflammation, elevated plasma homocysteine levels and cardiometabolic diseases. Multiple mechanisms have been proposed through which homocysteine can modulate the inflammatory response, though the exact mechanism is not clearly understood. The serum homocysteine concentration is considered as an independent risk factor for many disease conditions including cardiovascular diseases (CVD). Epidemiological evidence indicates that moderate consumption of anthocyanins is associated with reduced risk of atherosclerosis and cardiovascular diseases. However, a clear relationship between anthocyanin and homocysteine has not yet been developed. Anthocyanins are water soluble blue, red, and purple pigments, present in the vacuolar sap of the epidermal tissues of plant parts. As therapeutic agents, they are well-accepted in folk medicine worldwide and are linked to a myriad of health benefits. Anthocyanins impart an amazing role in lessening inflammation in body tissues. The molecular mechanisms involved in anti-inflammatory activities include inhibition of pro-inflammatory enzymes, such as cyclooxygenase-2, lipoxygenase and inducible nitric oxide (NO) synthase, inhibition of NF-kB and activating protein-1 (AP-1) and activation of phase II antioxidant detoxifying enzymes, mitogen-activated protein kinase (MAPK), protein kinase C and nuclear factor-erythroid 2-related factor 2. This chapter discusses the interrelationship between hyperhomocysteinemia, inflammation and anthocyanins, as well as the mechanisms of action and anti-inflammatory role of anthocyanins in the prevention of cardiometabolic diseases.
Homocysteine (Hcy) is a sulfhydryl-containing amino acid which forms during the metabolism of methionine [1]. Hcy might go under further metabolisation by the sulfuration pathway to cysteine, or remethylated using either betaine or methyltetrahydrofolate, which is confined to the liver [2]. Hyperhomocysteinemia (HHcy) is a condition in which a high levels of Hcy is present in the body, moderate or severe increase in plasma Hcy beyond the range of 5–15 μmoL/L is a remarkable independent cardiovascular risk factor in adults correlated with stroke, coronary disease, peripheral artery disease [3], congestive heart failure, atherosclerosis, Alzheimer’s disease [4], cardiovascular diseases (CVD) [5, 6], venous thrombosis [7] as well as cardiovascular outcomes in dialysis patients [8]. High levels of Hcy are toxic to vascular endothelium inducing endothelium damage [9] which contribute in the development of atherosclerosis in diabetic [10] and nondiabetic subjects [11]. It was also reported that HHcy plays an essential role in oxidative stress, endothelial dysfunction, endoplasmic reticulum (ER) stress and induction of inflammation [12]. In adults, high levels of plasma Hcy may induce a more rapid thickening of the intima-media layer in hypertension subjects [6]. Many studies were presented explaining the causal relationship between obesity and HHcy; in this chapter, we will highlight the previously conducted studies to understand the molecular mechanisms underlying the relationship between obesity and HHcy which is summarised in Fig. 13.1.
Dietary proteins metabolism involves the production of homocysteine which result from methionine as a sulfur-containing amino acid. Elevated levels of plasma homocysteine are associated with high risk of cardiovascular diseases. However, Previous studies indicate that plasma homocysteine can be used as a tumor marker and can be considered as a risk factor for cancer. The levels of homocysteine in the plasma is highly controlled by diet and several strategies were suggested for lowering plasma homocysteine. In this chapter, homocysteine biosynthesis and metabolism were explained. Diseases associated with hyperhomocysteinemia were discussed with special emphasis on cancer. Various natural products and dietary interventions were evaluated for their anticancer effects through lowering plasma homocysteine. This chapter will provide a solid ground for researchers to understand the link between hyperhomocysteinemia and cancer and the possible role of diet and natural product in lowering plasma homocysteine.
Background
We pursued to find out the possible association of Methylene tetrahydrofolate reductase (MTHFR) A1298C gene polymorphism, blood homocysteine, vitamin B12, and folate with Coronary artery disease (CAD) in the study population in Guilan, north of Iran.
Material and Methods
Ninety patients with CAD and 76 healthy controls were evaluated. MTHFR A1298C polymorphism and its genotype frequency, the plasma level of homocysteine, vitamin B12 and folate were evaluated by using ARMS-PCR, ELISA, and Chemiluminescence methods, respectively.
Results
The frequency of genotypes, A, AC and CC in CAD were 40, 35.6, 24.4%, respectively which was significantly different (p=0.016) from the control group that were 26.3, 57.9 and 15.8%, respectively. The serum level of vitamin B12 and folate in genotype A1298C were not statistically significant between two groups (p>0.05), however, the plasma homocysteine in patients with CAD was remarkably higher than the control group (p<0.001). Additionally, in CAD patients the plasma level of homocysteine in the AC genotype was significantly higher than the control subjects (p=0.005).
Conclusion
It is thus concluded that MTHFR A1298C gene polymorphism is associated with CAD. It seems that the AC genotype of MTHFR A1298C polymorphism might have a protective effect on CAD.
Elevated blood homocysteine (Hcy) is an independent risk factor for cardiovascular disease. A growing number of studies have evaluated the link between air pollution and blood Hcy levels, but the results are inconsistent. To date, no systematic review of the published studies has been conducted yet. We aimed to provide a comprehensive overview of these studies. We systematically searched three international databases (PubMed, Web of Science, and Embase) and four Chinese databases (Wanfang, CNKI, CBM, and VIP) for peer-reviewed epidemiological studies investigating associations between ambient air pollutants and Hcy levels published before December 2019. We screened literature, extracted data, assessed methodological quality, and evaluated the risk of bias of the included studies. Of 1157 identified articles, 10 were finally included in this systematic review. Most were cross-sectional studies and were performed in developed countries. Particulate matter with aerodynamic diameters less than 2.5 μm (PM2.5) and/or 10 μm (PM10) were investigated in all of the included studies.. Overall, the evidence generally supports a positive association between higher PM concentrations and elevated Hcy levels. However, high heterogeneity in terms of study participants, study design, exposure duration, and particle components and sources, low methodological quality and probable high risk of bias in some studies, and limited literature number precluded us from drawing a robust conclusion. Associations between Hcy and gaseous pollutants were explored in only one or two studies, and the results were inconclusive. Additional, well-designed studies remain required to validate the association between air pollution and Hcy.
Limited research is available on the possible differences in the cardiovascular risk factors of total homocysteine (tHcy), dietary energy, and lipids among adolescents with type 1 diabetes mellitus (DM), type 2 DM, or healthy controls. This study's primary aim was to compare the dietary energy and the intake of macronutrients and micronutrients of folate, and vitamins B6 and B12, as well as lipids and tHcy for adolescents with type 1 DM, type 2 DM, and healthy non-DM controls.
This secondary analysis of the merging of 2 datasets included the following adolescents: 50 with type 1 DM, 14 with type 2 DM, and 53 controls. Mean ages for those with type 1 versus type 2 DM were 15.2 +/- 1.9 versus 16.1 +/- 1.9 years, respectively. Mean age for the controls was 16.5 +/- 1.0 years. Variables included fasting tHcy and lipids, and 24-hour dietary recalls for macronutrients and micronutrients. Hemoglobin A1c was obtained for those with DM. Statistical analyses included one-way analyses of variance, Pearson correlations, and stepwise regression.
Adolescents with type 1 DM had the lowest tHcy values (P <.05), which were reflective of the limited extant research with this population. Lipid profiles and dietary energy did not differ significantly among the 3 groups. Hemoglobin A1c was related to total cholesterol and triglycerides in those with type 1 DM, confirming the importance of promoting better metabolic control in lipid management for these youth. Future research should continue to explore the validity of tHcy and lipids as predictors of CV risks for youth with type 1 and type 2 DM.
Supramolecular complexation of two bio-thiols, homocysteine (Hcys) and cysteine (Cys), by cucurbit[7]uril (CB[7]) has been fully investigated by ¹H NMR spectroscopy, mass spectrometry, isothermal titration calorimetry, and the results were further verified with computational investigations. NMR titration experimental results obviously indicate that the binding stoichiometry of CB[7] to Hcys is 1:1 and to Cys is 1:2 in aqueous solution. The binding constants and thermodynamic parameters associated with the complexation between CB[7] and the bio-thiols were determined by isothermal titration calorimetry. The energy-minimized structures of the supramolecular complexes of CB[7] with Hcys and Cys were determined and provide good agreement with the experimental results. The CB[7] cavity is sufficient to include the two Cys, but is unable to accommodate two Hcys due to steric hindrance. The differing binding abilities of Hcys and Cys in aqueous solution towards CB[7] host may lead to discriminate them.
Background:
Myocardial fibrosis is a major pathophysiologic substrate of heart failure with preserved ejection fraction. Vasopressin is an important therapeutic target in heart failure with preserved ejection fraction since it can modulate fluid balance, and based on a few studies, myocardial matrix deposition. Hence we examined the role of vasopressin antagonism in modulating myocardial matrix metabolism in vivo and in vitro.
Materials and methods:
In vivo studies utilized an established model of hyperhomocysteinemia-induced myocardial fibrosis in Sprague-Dawley rats combined with high salt diet; in vivo studies also utilized the same profibrotic stimuli of homocysteine and NaCl in cultured rat cardiac fibroblasts.
Results:
Hyperhomocysteinemia combined with high-salt diet promoted myocardial fibrosis, profibrotic and matrix gene expression and tolvaptan attenuated all these in vivo effects. In cultured cardiac fibroblasts, combined treatment with homocysteine and NaCl increased profibrotic and matrix gene expression and activation of PI3/Akt pathway; all these effects were attenuated by tolvaptan Vasopressin levels, gene expression and V2 receptor expression were increased in vivo and in vitro on exposure to profibrotic stimuli, and tolvaptan attenuated these in vivo and in vitro effects.
Conclusions:
Antagonism of vasopressin V2 receptor, via direct actions on cardiac fibroblast, attenuates myocardial matrix deposition.
The reaction between a reduced form of cobalamin (cobalamin(II), Cbl(II)) and periodate in alkaline medium is studied. It is shown that there is no destruction of cobalamin at the ratio of [Cbl(II)] : [IO\(_{4}^{ - }\)] = 2 : 1. The reaction mechanism includes interactions between Cbl(II) and H4IO\(_{6}^{ - }\) and H3IO\(_{6}^{{2 - }}\) leading to the formation of aquacobalamin and radicals I(VI), which rapidly oxidize the second molecule of Cbl(II) to aquacobalamin.
Background
Folic acid fortification program has been established to prevent tube defects. However, concern has been raised among patients using anti-folate drug, i.e. psoriatic patients, a common, chronic, autoimmune inflammatory skin disease associated with obesity and smoking.
Objective
To investigate dietary and circulating folate, vitamin B12 (B12) and homocysteine (hcy) in psoriatic subjects exposed to the national mandatory folic acid fortification program.
Methods
Cross-sectional study using the Food Frequency Questionnaire, plasma folate, B12, hcy and psoriasis severity using the Psoriasis Area and Severity Index score. Median, interquartile ranges (IQRs) and linear regression models were conducted to investigate factors associated with plasma folate, B12 and hcy.
Results
82 (73%) mild psoriasis, 18 (16%) moderate and 12 (11%) severe psoriasis. 58% female, 61% non-white, 31% former smokers, and 20% current smokers. Median (IQRs) were 51 (40, 60) years. Only 32% reached the Estimated Average Requirement of folate intake. Folate and B12 deficiencies were observed in 9% and 6% of the blood sample respectively, but hyperhomocysteinaemia in 21%. Severity of psoriasis was negatively correlated with folate and B12 concentrations. In a multiple linear regression model, folate intake contributed positively to 14% of serum folate, and negative predictors were psoriasis severity, smoking habits and saturated fatty acid explaining 29% of circulating folate.
Conclusion
Only one third reached dietary intake of folate, but deficiencies of folate and B12 were low. Psoriasis severity was negatively correlated with circulating folate and B12. Stopping smoking and a folate rich diet may be important targets for managing psoriasis.
The relation between vitamin nutritional status and circulating plasma homocyst(e)ine concentrations is reviewed. Several studies have shown that plasma concentrations of folate, vitamin B12 and pyridoxal 5′‐phosphate are inversely associated with plasma total homocyst(e)ine concentrations. Of the three vitamins mentioned above, folate is the most powerful homocyst(e)ine lowering agent and a daily supplement of 0.65 mg/day is sufficient to normalize moderate hyperhomocyst(e)inaemia in most individuals with normal renal function. In patients with severe renal failure, high doses of folate are required to treat hyperhomocyst(e)inaemia. Folic acid is ineffective in reducing plasma total homocyst(e)ine concentrations in patients with a vitamin B12 deficiency. Vitamin B6 supplementation has no effect on fasting plasma total homocyst(e)ine concentrations, but attenuates the post‐methionine load plasma homocyst(e)ine peak.
At least one report has shown that some individuals appear to be unable to maintain plasma total homocyst(e)ine concentrations in the normal reference range by a dietary intake of folic acid only. Long‐term vitamin supplementation may be indicated in these individuals. However, the clinical benefit of vitamin supplementation has not yet been demonstrated and controlled trials are urgently required.
This review of recent advances covers (1) the metabolism of methionine and its regulation, emphasizing interactions with the three important vitamins folate, cobalamin and pyridoxine; (2) present knowledge of enzymological and molecular‐genetic aspects of homozygous deficiencies of the three enzymes which cause elevated homocyst(e)ine; (3) recent clinical findings, post‐methionine loading results related to enzyme and mutation studies in obligate heterozygotes for cystathionine β‐synthase deficiency; (4) important new evidence for disturbed homocysteine metabolism in neural tube defects, particularly based on studies of the thermolabile methylene‐tetrahydrofolate reductase mutation which is also of importance in vascular disease; (5) the suitability and limitations of animal models that have so far been described.
Moderate elevation of plasma total homocysteine (tHcy) is a strong and independent risk factor for coronary artery disease (CAD). It can result from genetic or nutrient-related disturbances in the transsulfuration or remethylation pathways for Hcy metabolism. A point mutation (C677T; Ala-to-Val) in the gene encoding the 5,10-methylenetetrahydrofolate reductase (MTHFR) has been recently reported to render the enzyme thermolabile and less active. Studies on the role of this mutation as a risk factor for CAD have given conflicting results. We studied a total of 415 subjects, 278 with angiographically documented multivessel CAD and 137 with angiographically documented normal coronary arteries. The overall frequency of the MTHFR V/V homozygous genotype was 15.7% (with 52.5% heterozygous and 31.8% normal). Subgroup analysis showed no significant differences between CAD and CAD-free subjects. A genotype/phenotype correlation study showed a marked effect of folate on the association between MTHFR genotypes and tHcy. Among individuals with folate levels below the median (11.5 nmol/L), fasting tHcy was significantly increased not only in V/V homozygotes (by 59%) but also, at intermediate values, in A/V heterozygotes (by 21% on average). Conversely, the mutation resulted neutral with respect to tHcy levels in subjects with adequate folate levels. We conclude that, in our population, the MTHFR C677T mutation is rather common, but it does not appear to be associated per se to CAD. A genetic-environmental interaction may contribute to the vascular risk by elevating tHcy when folate status is low.
Elevated blood levels of homocysteine are associated with atherosclerosis and thrombotic disease. We previously reported that treatment of cultured endothelial cells with homocysteine increased endogenous factor V activity by activation of the cofactor. Because endothelial cell-associated factor Va would be regulated by the protein C mechanism, the ability of homocysteine-treated arterial and venous endothelial cells to activate protein C was investigated. Both arterial and venous endothelial cells activated protein C; 0.6 mmol/L homocysteine reduced endothelial cell protein C activation by 12%. Maximal inhibition (90%) of protein C activation occurred with 7.5 to 10 mmol/L homocysteine after 6 to 9 hours of incubation. Metabolism of homocysteine was not accelerated by cultured endothelial cells. Investigation of the mechanism(s) by which homocysteine reduced protein C activation indicated that the metabolite did not induce an inhibitor to activated protein C, but in low concentrations acted as a competitive inhibitor to thrombin. These data suggest that perturbation of the vascular endothelial cell protein C mechanism by homocysteine may contribute to the thrombotic tendency seen in patients with elevated blood levels of this metabolite.
Thrombomodulin plays a role as a cofactor for thrombin-catalyzed activation of protein C on endothelial cells. We examined the effect of homocysteine, a stimulant of atherosclerosis and thrombotic disease, on the cofactor activity and protein level of thrombomodulin and also on the expression of thrombomodulin in endothelial cells. Homocysteine inhibited the cofactor activity of thrombomodulin both on the surface of endothelial cells and in the whole cells dose- and time-dependently, and maximal inhibition of the cofactor activity occurred after a 3- to 6-hour incubation with 10 mmol/L homocysteine (10% of initial activity). Homocysteine also decreased the amount of intact (unreduced) thrombomodulin in endothelial cells. However, at the same condition the total protein level (reduced and unreduced form) of thrombomodulin, determined by dot immunoblot analysis using the monoclonal antibody that recognized both reduced and unreduced thrombomodulin, decreased slightly, and the mRNA level of thrombomodulin showed a twofold to three-fold increase. After 24 hours of incubation, the cofactor activity and total protein level of thrombomodulin were 60% and 165% of the initial values, respectively. When purified thrombomodulin fixed to a microwell plate was treated with homocysteine, both cofactor activity and thrombin-binding ability to the thrombomodulin were decreased in proportion to the concentration of homocysteine. These findings suggest that homocysteine directly inhibited the cofactor activity of thrombomodulin on endothelial cells by reducing the disulfide-bond rich epidermal growth factor-like structures of thrombomodulin. This would a result in the decrease of the antithrombotic property of endothelium and may also trigger off the synthesis of mRNA and protein of thrombomodulin to maintain the antithrombotic properties of the cells.
Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.
Mild hyperhomocysteinemia is accepted as a risk factor for premature cardiovascular disease. In a population with a high prevalence of cardiovascular disease, we screened a group of clinically healthy working men aged 30-49 y (n = 509) for plasma homocysteine and 5,10-methylene tetrahydrofolate reductase (MTHFR) genotype status. Those with mildly elevated homocysteine concentrations (> or = 8.34 micromol/L) were selected for intervention. In a randomized, factorial-design, controlled trial we assessed the effects of B-group vitamins and antioxidant vitamin supplementation on homocysteine concentrations. The 132 men were randomly assigned to one of four groups: supplementation with B-group vitamins alone (1 mg folic acid, 7.2 mg pyridoxine, and 0.02 mg cyanocobalamin), antioxidant vitamins alone (150 mg ascorbic acid, 67 mg RRR-alpha-tocopherol, and 9 mg beta-carotene), B-group vitamins with antioxidant vitamins, or placebo. Intervention was double-blind. A total of 101 men completed the 8-wk intervention. When homocysteine concentrations were analyzed by group, significant (P < 0.001) decreases (32.0% and 30.0%, respectively) were observed in both groups receiving B-group vitamins either with or without antioxidants. The effect of B-group vitamins alone over 8 wk was a reduction in homocysteine concentrations of 27.9% (95% CI: 22.0%, 33.3%; P < 0.001) whereas antioxidants alone produced a nonsignificant increase of 5.1% (95% CI: -2.8%, 13.6%; P = 0.21). There was no evidence of any interaction between the two groups of vitamins. The effect of B-group vitamin supplementation seemed to depend on MTHFR genotype. Supplementation with the B-group vitamins with or without antioxidants reduced homocysteine in the men with mildly elevated concentrations, and hence may be effective in reducing cardiovascular risk.
Objective To establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss. Design In a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test. Setting Gynecologic outpatient department of university hospital. Patients One-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected. Interventions Blood samples were collected just before and 6hours after oral methionine administration to determine plasma total homocysteine concentrations. Main Outcome Measure Plasma total homocysteine concentrations 6hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6hours exceeding the 97.5 percentile level of the controls. Results Hyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively). Conclusion Hyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.
Background:
Increased interest in the potential cardio-protective effects of fruit and vegetables is currently unsupported by systematic reviews of the reported associations of these foods with risk.
Method:
All ecological, case-control, cohort studies and unconfounded trials in humans were eligible for inclusion. Eligible outcomes were symptomatic coronary heart disease, stroke and total circulatory disease. Only studies of diet that reported on fresh fruit and vegetables or a nutrient which could serve as a proxy (reversing the usual direction of inference) were included. MEDLINE (1966-1995) and EMBASE (1980-1995) were searched using the terms cerebrovascular disorder, coronary heart disease, fruit(s) and vegetable(s) as keywords. Personal bibliographies, books and reviews were also searched, as were citations in located reports.
Results:
For coronary heart disease nine of ten ecological studies, two of three case-control studies and six of 16 cohort studies found a significant protective association with consumption of fruit and vegetables or surrogate nutrients. For stroke three of five ecological studies, none (of one) case-control study and six of eight cohort studies found a significant protective association with consumption of fruit and vegetables or surrogate nutrients. For total circulatory disease, one of two cohort studies reported a significant protective association. No attempt was made to arrive at a summary measure of the association because of the differences in study type, study quality and the different exposure measures used.
Conclusions:
Although null findings may be underreported the results are consistent with a strong protective effect of fruit and vegetables for stroke and a weaker protective effect on coronary heart disease. Greater use of food-based hypotheses and analyses, would complement existing nutrient-based analyses and help guide the search for underlying causes.
In Reply.
—Dr Braun is correct in indicating the RR for coronary heart disease for the lowest folate level studied was statistically significant (P=.04) for women, but not for men. However, the test for trend was statistically significant for both men and women. Although stratum-specific RRs were higher for women compared with men, the 95% CIs around the point estimates for men and women overlapped. Moreover, a comparison of the sex-specific rate ratios is not the most appropriate means to assess interaction. To formally test the interaction of sex, folate, and coronary heart disease, we compared the goodness-of-fit of a model that incorporated this interaction with one that did not. The deviances were 581.76 and 584.53 for the "interaction" and "no-interaction" models, respectively. This difference can be assumed to follow a X2 distribution with degrees of freedom equal to the difference in the number of independent parameters in the 2
We have prepared antibodies against porcine liver BHMT, and recently cloned cDNAs encoding the porcine and human enzyme. Porcine tissues were tested for BHMT expression by enzyme activity measurements, and Western analysis. Porcine liver and kidney were the only organs that had immune-detectable levels of BHMT protein, and expressed high levels of enzyme activity. Porcine pancreas, brain, heart, lung, and spleen were essentially devoid of enzyme activity and had no immuno-detectable protein. Both BHMT activity measurements and Western analysis indicate that BHMT is expressed in porcine kidney cortex, and not the medulla. Human tissues were tested for BHMT expression by Northern analysis. Human liver and kidney were the only organs that expressed BHMT mRNA. Human pancreas, brain, heart, skeletal muscle, spleen, and placenta were devoid of BHMT mRNA. BHMT was mapped to human chromosome 5 by PCR amplification using human BHMT-specific primers and chromosome specific human-rodent somatic cell hybrid panels. Refinement of the physical localization of the gene was obtained by screening a yeast artificial chromosome library. Funded by AHA (IL affiliate), and ILSI (N. America).
The Hordaland Homocysteine Study is a cohort of approximately 18,000 men and women, ages 40–67, who had their total plasma homocysteine (tHcy) determined in 1992 or 1993. The long-term aim of the study is to relate plasma tHcy to future cardiovascular disease incidence, cause-specific, and all-cause mortality. In Norway, complete mortality follow-up is assured for all individuals who do not leave the country permanently, and the study will have access to mortality data kept at the Central Bureau of Statistics. Furthermore, we plan to register all hospitalizations for cardiovascular disease, including coronary angiographies, coronary surgery, and balloon angioplasties in the six hospitals that serve Hordaland. Complete cancer incidence data for the cohort members will also be available through the Cancer Registry of Norway, which keeps records of all cancer cases diagnosed in the country. No follow-up data are available yet, and so far we have focused on the study of cross-sectional associations between plasma tHcy and established cardiovascular risk factors and lifestyle.
Background Hyperhomocysteinemia, an independent and graded risk factor for coronary artery disease (CAD), may result from both environmental and hereditary factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the methyl donor in the remethylation of homocysteine to methionine. A 677C→T mutation in the MTHFR gene has been associated with elevated homocysteine concentrations in homozygous (+/+) individuals.
Methods and Results We assessed the frequency of this common mutation in 735 CAD patients from the Regression Growth Evaluation Statin Study (REGRESS), a lipid-lowering coronary-regression trial, and in 1250 population-based control subjects. Furthermore, the association between the mutation and serum homocysteine concentrations was studied. The frequency of the homozygous (+/+) mutation was 9.5% among patients versus 8.5% among control subjects, resulting in an odds ratio of 1.21 (95% confidence interval [CI], 0.87 to 1.68), relative to the (−/−) genotype. Homocysteine concentrations were significantly elevated in both (+/+) and (+/−) individuals compared with (−/−) individuals (median homocysteine levels, 15.4, 13.4, and 12.6 μmol/L, for (+/+), (+/−), and (−/−) individuals, respectively). For a summary estimation of the risk of the (+/+) genotype for CAD, we performed a meta-analysis on 8 different case-control studies on thermolabile MTHFR in CAD. In the meta-analysis, the homozygous (+/+) genotype was present in 299 of 2476 patients (12.1%) and in 257 (10.4%) of 2481 control subjects, resulting in a significant odds ratio of 1.22 (95% CI, 1.01 to 1.47) relative to the (−/−) genotype.
Conclusions Both the homozygous (+/+) and heterozygous (+/−) genotype result in elevated homocysteine concentrations. From our meta-analysis, we conclude that the homozygous (+/+) genotype is a modest but significant risk factor for CAD.
Homocystinuria is an inborn error on the pathway of the metabolism of methionine due to an absence of cystathionine synthetase in brain and liver. Clinical experience with ten cases occurring in seven families shows a consistent picture characterized by mental retardation, ectopia lentis, fine, fair hair, malar flush, thromboembolic and cardiovascular disease, skeletal deformities, and fatty change of liver. Family pedigrees suggest an autosomal recessive mode of inheritance. There are increased amounts of methionine and homocystine in the plasma and cerebrospinal fluid with increased excretion of homocystine in the urine. Fragmentation of the elastic tissue of large arteries is accompanied by a decrease in the glycoprotein and protein polysaccharide matrix. The fatty change of liver is due to a twofold increase in the neutral lipids. The brain shows focal necrosis and gliosis, and there are degenerative changes of the zonular fibers of the lens on light and electron microscopy.
The oxidation of LDL is now commonly implicated as an initiator of atherosclerosis and a standard in-vitro LDL 'oxidizability' test is required. This review will discuss current problems and advances that have been made in our understanding of the molecular mechanisms of radical-mediated LDL oxidation and antioxidation, how they relate to the in-vitro assessment of the 'oxidizability' of LDL and how they may be relevant to in-vivo LDL oxidation. Tocopherol-mediated peroxidation is used as a novel model of LDL lipid oxidation to discuss why terms such as 'lag time' are features of the in-vitro oxidation conditions, rather than being inherent to LDL oxidation per se. In addition, we will also cover why it is premature, at present, to use one particular LDL oxidizability test as a standard.
Cystathionine β-synthase (CBS) deficiency is an autosomal recessive disorder which results in extremely elevated levels of total plasma homocysteine (tHcy) and high risk of thromboembolic events. About half of all patients diagnosed with CBS deficiency respond to pyridoxine treatment with a significant lowering of tHcy levels. We examined 12 CBS-deficient patients from 10 Norwegian families for mutations in the CBS gene and identified mutations in 18 of the 20 CBS alleles. Five of the seven patients classified as pyridoxine-responsive contain the newly identified point mutation, G 797 A (R266K). This point mutation is tightly linked with a previously identified 'benign' 68 bp duplication of the intron 7-exon 8 boundary within the CBS gene. We tested the effect of all of the mutations identified on human CBS function utilizing a yeast system. Five of the six mutations had a distinguishable phenotype in yeast, indicating that they were in fact pathogenic. Interestingly, the G 797 A allele had no phenotype when the yeast were grown in high concentrations of pyridoxine, but a severe phenotype when grown in low concentrations, thus mirroring the behavior in humans. These studies show that the G 797 A mutation is an important cause of pyridoxine-responsive CBS deficiency and demonstrate the utility of yeast functional assays in the analysis of human mutations.
BACKGROUND Vasoconstrictor responses to serotonin are augmented in monkeys with diet-induced atherosclerosis and improve after 18 months of normal diet. We tested the hypothesis that functional improvement may occur early during regression, before evidence of structural improvement.
METHODS AND RESULTS Responses of the iliac artery to serotonin were measured by quantitative angiography and a Doppler flow probe in several groups of monkeys: (1) normal monkeys, (2) monkeys fed an atherogenic diet for 2 years (atherosclerotic), and (3) monkeys fed an atherogenic diet for 2 years (preregression) followed by a normal diet for 4, 8, or 12 months (regression). In normal monkeys, serotonin produced minimal constriction of the iliac artery, and blood flow to the legs increased. In atherosclerotic monkeys, there was pronounced constriction of the iliac artery, and blood flow to the legs decreased markedly. After 4 months of regression diet, four of eight monkeys demonstrated marked reduction in hyperresponsiveness to serotonin angiographically, and by 8 months, six of eight monkeys had significant improvement. After regression, serotonin produced minimal changes in flow. There was no reduction in intimal area (ie, atherosclerotic lesion) in iliac arteries from regression monkeys compared with atherosclerotic monkeys, but there was a marked reduction in cholesteryl ester in arteries from regression monkeys.
CONCLUSIONS Abnormal vasoconstrictor responses to serotonin usually return to or toward normal within a few months during regression of atherosclerosis. Functional improvement occurs in conjunction with early resorption of lipid from the arterial wall and occurs before detectable changes in mass of the atherosclerotic lesion.
Objective.
—To assess the relationship between serum folate level and the risk of fatal coronary heart disease (CHD) among men and women.Design.
—Retrospective cohort study with serum folate levels measured from September 1970 to December 1972, with follow-up through 1985.Setting.
—Participants in the Nutrition Canada Survey.Participants.
—A total of 5056 Canadian men and women aged 35 to 79 years with no history of self-reported CHD.Main Outcome Measure.
—Fifteen-year CHD mortality.Results.
—A total of 165 CHD deaths were observed. We found a statistically significant association between serum folate level and risk of fatal CHD, with rate ratios for individuals in the lowest serum folate level category (<6.8 nmol/L [3 ng/mL]) compared with the highest category (>13.6 nmol/L [6 ng/mL]) of 1.69 (95% confidence interval, 1.10-2.61).Conclusions.
—These data indicate that low serum folate levels are associated with an increased risk of fatal CHD.(JAMA. 1996;275:1893-1896)
To the Editor.—
Although azaribine has been shown to be an effective drug in the treatment of psoriasis, the Food and Drug Administration has recently prohibited the use of this antimetabolite because of the possibility of an associated increased incidence of thromboembolism. We present a hypothesis and some preliminary supporting data that may explain this adverse effect.In 1969, high dosages of azaribine (400 mg/kg/day) were shown to result in the urinary excretion of various amino acids, including homocystine.1, 2 Until recently, this appeared to be a mere biochemical curiosity. However, with the report of vascular complications in patients who were on a regimen of azaribine, similar to those complications found in patients with hereditary homocystinuria, we screened our patients who were receiving azaribine for the presence of homocystine in the blood and the urine. As homocystine is normally not present in either the blood or the urine, detectable
Objective.
—To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake.Data Sources.
—MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels.Study Selection and Data Extraction.
—Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations.Data Synthesis.
—Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact.Conclusions.
—A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements.(JAMA. 1995;274:1049-1057)
Objective
—To describe the distribution of plasma homocysteine concentrations in an elderly population and to analyze the relationship between homocysteine level and intake of vitamins and serum levels of vitamins that serve as coenzymes in homocysteine metabolism.
Design
—Cross-sectional analysis of homocysteine levels and vitamin blood levels and intake in elderly participants in the Framingham Study.
Setting
—Population-based cohort in Framingham, Mass.
Participants
—A total of 1160 adult survivors, aged 67 to 96 years, from the original Framingham Heart Study cohort.
Main Outcome Measures
—Plasma homocysteine concentration correlated with plasma folate, vitamin B12, pyridoxal-5'-phosphate (PLP), and oral intakes of these vitamins, and the contribution of these vitamins to the prevalence of elevated homocysteine in the population.
Results
—Homocysteine levels were positively correlated with age after controlling for vitamin concentrations. After controlling for age, sex, and levels of other vitamins, homocysteine exhibited a strong inverse association with plasma folate. When subjects were grouped by deciles of plasma folate, mean homocysteine was significantly higher in the lowest two folate deciles (15.6 and 13.7 μmol/L, respectively) than in the highest decile (11.0 μmol/L). Homocysteine demonstrated weaker, inverse associations with plasma vitamin B12 and PLP. Similar inverse associations were demonstrated between homocysteine and intakes of folate and vitamin B6, but not vitamin B12. Prevalence of high homocysteine (>14 μmol/L) was 29.3% in this cohort, and was greatest among subjects with low folate status. Inadequate plasma concentrations of one or more B vitamins appear to contribute to 67% of the cases of high homocysteine.
Conclusions
—These results indicate a strong association between homocysteine concentration and folate, vitamin B12, and vitamin B6 status, as well as age. It is possible that a substantial majority of the cases of high homocysteine in this older population can be attributed to vitamin status.(JAMA. 1993;270:2693-2698)
The purpose of this study was to investigate H(e) concentration in plasma from 80 healthy donors in relation to age (6 newborns are also included), sex, daily variation (9, 11 a.m.; 2, 6, 12 p.m.) and a period of 5 subsequent months. A significant correlation (r = 0.63, p < 0.001) was observed between plasma H(e) and age and a statistical difference (p < 0.05) was found between female and male. No circadian rhythm or significant variations over 5 months were found.
Homocystinuria is an inborn error of metabolism involving a high incidence of thromboembolism. It sometimes improves with large doses of pyridoxine. We investigated the kinetics and distribution of ¹¹¹Indoxine-labeled platelets in 11 normal volunteers and 12 patients with homocystinuria, none of whom had clinical evidence of acute thrombosis at the time of the study. Six of the patients were resistant to pyridoxine and had homocystinemia. There were no statistical differences in mean platelet-survival times between pyridoxine responders and nonresponders or between normal subjects and pyridoxine responders or nonresponders, regardless of whether a linear, exponential, or multiple-hit model was used to analyze the kinetic data. Plasma homocystine levels had no apparent effect on mean platelet-survival time. There was no abnormal accumulation of platelets in any of the patients, and the distribution of platelets in liver and spleen was similar to that in normal subjects. Our results suggest that the kinetics and distribution of platelets in patients with homocystinuria who have no clinical evidence of thromboembolism are normal. Thus, the data do not provide evidence for disordered platelet function or for an ongoing interaction of platelets with vessel walls in this condition.
Homocystinuria due to cystathionine β-synthase (CBS) deficiency (EC 4.2.1.22, McKusick 236200) is a clinically and biochemically well defined disorder of sulphur amino acid metabolism (Mudd et al 1995). During the last twenty years our laboratory diagnosed CBS deficiency in 19 Czech and Slovak patients. The data show that CBS deficiency is the most frequent cause of severe hyperhomocysteinaemia among these Western Slavs, with an estimated incidence of 1:240000. The molecular basis of cystathionine β-synthase deficiency has been studied extensively by several groups in about 150 alleles worldwide, and over 50 different mutations have been found so far (J.P. Kraus, unpublished results). We have analysed the CBS gene in 12 Czech and Slovak homocystinuric patients and here we report the first results, including three novel mutations.