Decreased Homocysteine Levels Research Articles

Homocysteine and folate: from genes to greens

Several epidemiologic studies have shown correlations between mildly elevated homocysteine levels and cardiovascular disease risk. Hyperhomocysteinemia may be atherogenic or prothrombotic by various mechanisms. Whether mild to moderate hyperhomocysteinemia is a cause, consequence or marker of atherosclerotic vascular disease is still being questioned. The main determinants of plasma homocysteine levels are genetic and nutritional factors. MTHFR 677C>T polymorphism leading to reduced enzyme activity is an important genetic determinant of homocysteine levels. A recent meta-analysis involving more than 23,000 subjects has shown that individuals with the MTHFR 677 TT genotype have 16% higher risk of coronary disease compared with those with the CC genotype. The increase in risk is significant in Europeans but not in North Americans. This discrepancy can be explained by multivitamin intake, ethnic differences and other risk factors showing a typical gene–environment interaction. Folate intake is another determinant of plasma homocysteine levels and dietary supplementation with folic acid, vitamin B12 and B6 can reduce homocysteine concentrations to different extents. However, evidence linking folate and B vitamin levels to cardiovascular disease is inconclusive. Our studies have revealed that patients with the TT genotype and folate levels below the median of the population have the highest homocysteine levels and more extensive atherosclerosis as judged by the coronary angiogram. The important question of whether lowering homocysteine will decrease cardiovascular risk is being addressed by several randomized trials. Meanwhile, two recent trials questioning the effect of lowering homocysteine on restenosis—the Swiss Heart Study and the FACIT trial—have yielded largely discrepant results. Furthermore, a recent trial in patients with stable coronary disease showed that folate supplementation decreased homocysteine levels without having any impact on cardiovascular events. We will have to wait for the results of large randomized trials to see the impact of lowering homocysteine on cardiovascular risk.

Effects of paradoxical sleep deprivation on blood parameters associated with cardiovascular risk in aged rats

The effects of 96 h of paradoxical sleep deprivation (PSD) on blood parameters associated with cardiovascular risk were studied in young (3-month old) and aged (22-month old) rats. In general, aging was associated with an overall increase in most measures, irrespective of sleep deprivation condition. The latter manipulation also had significant effects on blood variables, but not in a consistent pattern. Thus, PSD significantly reduced triglyceride levels in both young and aged rats; it reduced blood viscosity in aged but not in young rats, and had no effect on the increased cholesterol levels observed in aged controls. Examinations of cholesterol fractions revealed significant increases in low density lipoprotein and high density lipoprotein in aged PSD rats compared to respective controls, whereas very low density lipoprotein was significant decreased after PSD in both young and aged animals. PSD increased vitamin B 12 levels in aged rats, and significantly decreased homocysteine levels in young but not in aged rats which in turn were already reduced. Folate levels were the only variable that was unaffected by aging and/or PSD. These results indicate that PSD has significant but heterogeneous physiological effects in aged rats and may intensify certain aging-related effects which contribute to cardiovascular disease risk while attenuating others.

Treatment of hyperhomocysteinemia after renal transplantation

Introduction Several epidemiologic prospective studies have provided strong evidence that hyperhomocysteinemia (HHC) is a risk factor for cardiovascular disease (CVD) due to its role in producing endothelial damage due to oxidation stress. Several studies show that combined folic acid (FA) and vitamin B12 (B12) treatment decreases fasting total homocysteine (HC) levels in renal transplant recipients (RTR). The aim of the study was to determine the efficacy and safety during one year of combined FA and B12 treatment in 89 RTR, as well as the relationship between HHC with other known risk factors for CVD and the intrinsic characteristics of the transplantation. Methods Among 193 RTR in whom we determined the baseline levels of HC, FA, B12, creatinine, and CV risk factors, 81 had normal (HC < 14 μmol/L) and 112 elevated (HC ≥ 14 μmol/L) HC levels, 89 of whom were included in a treatment group (23 nontreated). Analytic measures were performed at baseline and 1, 3, and 12 months. Results We observed a decrease in HC levels among the treatment group ( P < .05) after 12 months without differences in the other groups. There were no differences in age, hypertension, hypercholesterolemia, smoking, presence of diabetes, or type of immunosuppression between the groups. There was a significant correlation between basal creatinine and HC level ( P < .05). A higher prevalence of CVD was observed in the HHC group ( P < .05). Conclusion HHC is associated with worse renal function and a higher prevalence of CVD. FA and B12 treatment normalize HC levels, representing a safe treatment that could improve the long-term vascular prognosis of RTR.

Does homocysteine cause hypertension?

Several studies, some population-based, have plasma homocysteine levels linked to blood pressure, especially systolic pressure. In one large and carefully conducted epidemiological study, each 5 micromol/l increase in plasma homocysteine was associated with an increase in systolic and diastolic blood pressure of 0.7/0.5 mmHg in men and 1.2/0.7 mmHg in women, which was independent of renal function and B vitamin status. In addition, observations that homocysteine-lowering therapies with folic acid-based treatments have been followed by decreases in blood pressure raise the possibility that the link between homocysteine and blood pressure is causal, which is important since homocysteine levels can easily be lowered by folic acid-based regimens. Mechanisms that could explain the relationship between homocysteine and blood pressure include homocysteine-induced arteriolar constriction, renal dysfunction and increased sodium reabsorption, and increased arterial stiffness. However, there is only circumstantial evidence that these mechanisms are operative in humans. In addition, confounding by subtle renal dysfunction or by unmeasured dietary and lifestyle factors cannot be excluded as an explanation for the association between homocysteine and blood pressure. At present, therefore, the hypothesis that homocysteine increases blood pressure must be considered unproven. Ongoing large intervention studies with homocysteine-lowering vitamins may show whether blood pressure is indeed lowered by these vitamins, whether the blood pressure decrease, if any, is explained by the decrease in homocysteine levels, and whether a vitamin treatment-associated decrease in cardiovascular morbidity, if any, is explained by the decrease in blood pressure.

Homocysteine and blood pressure.

Several studies, some population-based, have linked plasma homocysteine levels to blood pressure, especially systolic pressure. The strength of this association is weak, but may be underestimated due to inaccurate blood pressure measurements. In addition, the association may be confounded by renal function. Observations that homocysteine-lowering therapies with folic acid-based treatments have been followed by decreases in blood pressure, however, raise the possibility that the link between homocysteine and blood pressure is real, which is important as homocysteine levels can easily be lowered by folic acid-based regimens. Mechanisms that could explain the relationship between homocysteine and blood pressure include increased arterial stiffness, endothelial dysfunction with decreased availability of nitric oxide, low folate status, and insulin resistance. So far, however, no evidence has been provided that these mechanisms are operative in humans. Ongoing large intervention studies with homocysteine-lowering vitamins may indicate whether blood pressure is indeed lowered by these vitamins, whether the blood pressure decrease, if any, is explained by the decrease in homocysteine levels, and whether a vitamin treatment-associated decrease in cardiovascular morbidity (if any) is explained by the decrease in blood pressure.

Homocysteine in neuropsychiatric disorders of the elderly.

There is increasing interest in homocysteine as a risk factor for neuropsychiatric disorders such as stroke, dementia, depression and Parkinson's disease. This article reviews the current literature on the relationship between homocysteine and these disorders to ascertain if any clinical recommendations can be made. A MEDLINE and EMBASE search was made for English language publications between 1966 and 2002 using the search terms 'Homocysteine' and 'Stroke', 'Dementia', 'Vascular Dementia', 'Alzheimer's dementia', 'Cognition disorders or cognitive decline or memory disorders', 'Depression or depressive disorders' or 'Parkinson's disease'. In addition, individual articles were hand searched for relevant references. Cross-sectional studies consistently suggest that elevated homocysteine increases the risk of stroke, and may also increase the risk of leukoariosis, vascular dementia (VaD), cognitive impairment and Alzheimer's disease (AD). Longitudinal studies of homocysteine as a risk factor are few and inconsistently supportive of these associations. No intervention trials to determine the effect of lowering homocysteine levels have yet been published. The pathological mechanisms for homocysteine-mediated disease await complete elucidation. Mild hyperhomocysteinemia is common in the elderly population, and folate supplementation can decrease homocysteine levels. The epidemiological evidence for homocysteine as a risk factor for neuropsychiatric disease is an emerging area of great interest. Screening the population for hyperhomocysteinemia cannot be recommended at this stage, but individuals at increased risk of cerebrovascular disease or cognitive impairment should be investigated and treated for elevated homocysteine levels.

Sleep deprivation reduces total plasma homocysteine levels in rats.

Hyperhomocysteinemia has been associated with pathological and stressful conditions and is a risk factor for cardiovascular disease. Since sleep deprivation is a stressful condition that is associated with disruption of various physiological processes, we investigated whether it would also be associated with increases in plasma homocysteine levels. Further, since hyperhomocysteinemia may promote oxidative stress, and we had previously found evidence of oxidative stress in brain following sleep deprivation, we also searched for evidence of systemic oxidative stress by measuring glutathione and thiobarbituric acid reactive substance levels. Rats were sleep deprived for 96 h using the platform technique. A group was killed after sleep deprivation and another two groups were allowed to undergo sleep recovery for 24 or 48 h. Contrary to expectation, plasma homocysteine was reduced in sleep-deprived rats as compared with the control group and did not revert to normal levels after 24 or 48 h of sleep recovery. A trend was observed towards decreased glutathione and increased thiobarbituric acid reactive substance levels in sleep-deprived rats. It is possible that the observed decreases in homocysteine levels may represent a self-correcting response to depleted glutathione in sleep-deprived animals, which would contribute to the attenuation of the deleterious effects of sleep deprivation.

The effect of folic acid, vitamin B6 and vitamin B12 on the homocysteine levels in rabbits fed by methionine-enriched diets.

Atherosclerosis is an important cause of cardiovascular morbidity and mortality in recent years. Hyperhomocysteinemia is recognized as an independent risk factor for premature atherosclerosis and venous thrombosis. It is suggested that administration of folic acid, vitamin B6 and vitamin B12 may decrease homocysteine levels. In our study, we induced hyperhomocysteinemia in rabbits by giving methionine and studied the effects of folic acid, vitamin B6 and vitamin B12 on homocysteine levels. A total of 40 (20 female, 20 male New Zealand rabbits) were divided into four groups, each consisting of 10 rabbits. Methionine (100 mg/kg/day), methionine (100 mg/kg/day) plus vitamin B6 (30 mg/kg/day), methionine (100 mg/kg/day) plus vitamin B12 (80 mg/kg/day) and methionine (100 mg/kg/day) plus folic acid (20 mg/kg/day) were given to the first, second, third and forth groups respectively. These rabbits were followed up for two months. We studied homocysteine levels on the 0, 20th, 40th and 60th days in all groups. In rabbits we induced hyperhomocysteinemia by giving methionine for 2 months. The decreases of homocysteine levels in the forth group were significant with respect to the second and third groups. Folic acid supplementation clearly resulted in a reduction of plasma homocysteine levels, whereas vitamin B12 was little effective and vitamin B6 failed to show an effect. We conclude that even folic acid treatment alone may be sufficient for decreasing negative effects of homocysteine.

The effect of hormone replacement therapy on serum homocysteine levels in perimenopausal women: a randomized controlled trial

Serum homocysteine levels may be lowered by hormone replacement therapy, but randomized controlled trial data are scarce. We performed a single center randomized placebo-controlled trial to assess the 6 months effect of hormone replacement therapy compared with placebo on fasting serum homocysteine levels in 121 perimenopausal women free of cardiovascular disease, and recruited from the general population. The trial was double-blind with respect to a sequential combined regimen of oral 17β-estradiol and desogestrel (17βE 2-D) and the placebo group and open with respect to a combination of conjugated equine estrogens and norgestrel (CEE-N). At baseline and after 6 months, fasting serum homocysteine levels were measured. Differences in 6 months serum homocysteine levels from baseline between treatment and placebo groups were calculated, and expressed as a percentage of the 6 months placebo level. After 6 months, the difference in serum homocysteine levels between women receiving 17βE 2-D and placebo was −6.3% (95% CI, −12.4%; 0.0%, P=0.06). The difference between women receiving CEE-N and placebo was −10.1% (95% CI, −16.7%; −2.9%, P<0.01). The difference between the combined group of both types of hormone replacement therapy users and placebo was −7.8% (95% CI, −13.2%; −2.0%, P=0.01). No significant difference was observed between the two active regimens. Our results indicate that hormone replacement therapy decreases homocysteine levels in perimenopausal women.

Does Homocysteine Promote Atherosclerosis?

The hypothesis that homocysteine is atherogenic was proposed more than 30 years ago by Kilmer McCully,1 who observed vascular lesions in children with inherited disorders of methionine metabolism. Since McCully’s pioneering observations in 1969, a large number of epidemiological studies have confirmed that an elevation of total plasma homocysteine (tHcy) is prevalent in patients with stroke, myocardial infarction, peripheral vascular disease, and venous thrombosis.2 A significant association between hyperhomocysteinemia and clinical cardiovascular events has been observed in several large prospective studies, although a few prospective studies have failed to demonstrate this association.2 Nevertheless, hyperhomocysteinemia is now considered by many an independent risk factor for atherosclerotic vascular disease.3 See p 1470 Homocysteine is a thiol amino acid, but only a small fraction ( 15 μmol/L and may be caused by genetic defects, renal insufficiency, certain drugs, or nutritional deficiencies of folate, vitamin B6, or vitamin B12.5 Even a mild elevation of plasma tHcy to levels within the high-to-normal range (10 to 15 μmol/L) may increase cardiovascular risk.2 Because plasma tHcy can often be lowered by oral administration of folic acid or combinations of B vitamins, there is growing enthusiasm for treatment of hyperhomocysteinemia as a strategy for prevention of cardiovascular disease and …

E Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

e Renal Vein Thrombosis, Oral Contraceptive Use, and Hyperhomocysteinemia

Potential New Cardiovascular Risk Factors: Left Ventricular Hypertrophy, Homocysteine, Lipoprotein(a), Triglycerides, Oxidative Stress, and Fibrinogen

The 1996 Bethesda Conference acknowledged left ventricular hypertrophy, hyperhomocysteinemia, lipoprotein(a) excess, hypertriglyceridemia, oxidative stress, and hyperfibrinogenemia as possible new cardiac risk factors. This review summarizes the current literature that supports these conditions as cardiac risk factors. Left ventricular hypertrophy is an independent risk factor for vascular disease. Improvement or progression of left ventricular hypertrophy influences subsequent cardiovascular complications. Clinical trials are under way to assess the potential benefit of decreasing homocysteine levels. The role of lipoprotein(a) excess in vascular disease is controversial. The atherogenic potential of lipoprotein(a) seems to be neutralized by effective reduction of low-density lipoprotein cholesterol levels. Increasing evidence supports an independent role of hypertriglyceridemia in cardiovascular disease and a possible clinical benefit from decreasing triglyceride levels. Among antioxidant micronutrients, supplementation with vitamin E has been shown to be beneficial in primary and secondary prevention studies. Data supporting the use of other antioxidants are much weaker. Preliminary evidence suggests that reducing fibrinogen levels in patients with high baseline levels and coronary disease may be beneficial. Despite the potential relation between new risk factors and cardiovascular disease, routine clinical application of these conditions as cardiovascular risk factors would be premature. Evidence is needed that these conditions extend prognostic ability beyond conventional risk factors and that modification of these conditions can reduce the risk for cardiovascular events.

The structure and properties of methylenetetrahydrofolate reductase from Escherichia coli suggest how folate ameliorates human hyperhomocysteinemia.

Elevated plasma homocysteine levels are associated with increased risk for cardiovascular disease and neural tube defects in humans. Folate treatment decreases homocysteine levels and dramatically reduces the incidence of neural tube defects. The flavoprotein methylenetetrahydrofolate reductase (MTHFR) is a likely target for these actions of folate. The most common genetic cause of mildly elevated plasma homocysteine in humans is the MTHFR polymorphism A222V (base change C677-->T). The X-ray analysis of E. coli MTHFR, reported here, provides a model for the catalytic domain that is shared by all MTHFRs. This domain is a beta8alpha8 barrel that binds FAD in a novel fashion. Ala 177, corresponding to Ala 222 in human MTHFR, is near the bottom of the barrel and distant from the FAD. The mutation A177V does not affect Km or k(cat) but instead increases the propensity for bacterial MTHFR to lose its essential flavin cofactor. Folate derivatives protect wild-type and mutant E. coli enzymes against flavin loss, and protect human MTHFR and the A222V mutant against thermal inactivation, suggesting a mechanism by which folate treatment reduces homocysteine levels.