ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins

OBJECTIVES: Hyperhomocyst(e)inemia is a risk factor for atherosclerotic vascular disease, and it is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of NO, possibly secondary to accumulation of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) and increased oxidative stress. We investigated whether oral treatment with B vitamins or L-arginine normalizes endothelium-dependent, flow-dependent vasodilation (FDD) in patients with peripheral arterial occlusive disease (PAOD) and hyperhomocyst(e)inemia. METHODS: 27 patients with PAOD and hyperhomocyst(e)inemia were assigned to oral treatment with combined B vitamins (folate, 10 mg; vitamin B-12, 200 microg; vitamin B-6, 20 mg/day), L-arginine (24 g/day) or placebo, for 8 weeks in a double-blind fashion. FDD was determined by high-resolution ultrasound in the radial artery. RESULTS: Vitamin B supplementation significantly lowered plasma homocyst(e)ine concentration from 15.8+/-1.8 to 8.7+/-1.1 micromol/l (P<0.01). However, B vitamins had no significant effect on FDD (baseline, 7.8+/-0.7%, B vitamins, 8.3+/-0.9%, placebo 8.9+/-0.7%; P=n.s.). In contrast, L-arginine treatment did not affect homocyst(e)ine levels, but significantly improved FDD (10.2+/-0.2%), probably by antagonizing the impact of elevated ADMA concentration (3.8+/-0.3 micromol/l) and reducing the oxidative stress by lowering urinary 8-iso-prostaglandin F(2alpha) (baseline, 76.3+/-7.1 vs. 62.7+/-8.3 pmol/mmol creatinine after 8 weeks). CONCLUSIONS: Oral supplementation with combined B vitamins during 8 weeks does not improve endothelium-dependent vasodilation in PAOD patients with hyperhomocyst(e)inemia, whereas L-arginine significantly improved endothelial function in these patients. Thus, accumulation of ADMA and increased oxidative stress may underlie endothelial dysfunction under hyperhomocyst(e)inemic conditions. These findings may have importance for evaluation of homocyst(e)ine-lowering therapy.     

Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia

Hyperhomocyst(e)inemia is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of endothelium-dependent nitric oxide. We tested the hypothesis that hyperhomocyst(e)inemia is associated with an elevated plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. One group of adult cynomolgus monkeys was fed either a control or hyperhomocyst(e)inemic diet for 4 weeks in a randomized crossover design. The second group was fed an atherogenic diet that produces both hyperhomocyst(e)inemia and hypercholesterolemia for 17 months, followed by an atherogenic diet supplemented with B vitamins for 6 months to decrease plasma homocyst(e)ine concentration. Human endothelial cells were used to study the effects of methionine and homocysteine in the presence or absence of B vitamins or the methylation inhibitor S-adenosylhomocysteine on the formation of ADMA and its inactive stereoisomer, symmetric dimethylarginine. The hyperhomocyst(e)inemic diet produced 2- to 3-fold increases in plasma levels of homocyst(e)ine and ADMA (both P<0.05). The atherogenic diet also produced elevated plasma levels of homocyst(e)ine and ADMA (both P<0. 05). Supplementation of the atherogenic diet with B vitamins decreased the plasma levels of homocyst(e)ine but did not affect the plasma levels of ADMA or endothelial function. There was a strong correlation between plasma ADMA and homocyst(e)ine and a strong inverse correlation between ADMA and carotid artery relaxation to acetylcholine. ADMA release by cultured endothelial cells was significantly increased in the presence of methionine or homocysteine. This effect was blocked by S-adenosylhomocysteine but not by B vitamins. We conclude that plasma levels of ADMA are elevated in hyperhomocyst(e)inemia. Because ADMA acts as a competitive inhibitor of endothelial nitric oxide synthase, these findings suggest a novel mechanism for impaired endothelial function in hyperhomocyst(e)inemia.     

HYPERHOMOCYST(E)INEMIA: A RISK FACTOR FOR CEREBROVASCULAR DISEASE

Many case-control and cohort studies have identified a strong, independent and dose-related association between moderate hyperhomocyst(e)inemia and atherosclerotic vascular disease, with respect to the pathogenetic link between hyperhomocyst(e)inemia and stroke, the possible role in inducing an endothelial wall damage deserves special attention. Some prospective cohort studies have failed to demonstrate a positive association between elevated homocyst(e)ine (Hcy) levels and stroke. Further studies are needed, in order to better characterize the association between Hcy concentrations and risk of stroke.     

Hyperhomocyst(e)inemia: a risk factor for cerebrovascular disease

Many case-control and cohort studies have identified a strong, independent and dose-related association between moderate hyperhomocyst(e)inemia and atherosclerotic vascular disease, with respect to the pathogenetic link between hyperhomocyst(e)inemia and stroke, the possible role in inducing an endothelial wall damage deserves special attention. Some prospective cohort studies have failed to demonstrate a positive association between elevated homocyst(e)ine (Hcy) levels and stroke. Further studies are needed, in order to better characterize the association between Hcy concentrations and risk of stroke.     

Hyperhomocyst(e)inemia

Opinion Statement Hyperhomocyst(e)inemia is under scrutiny as a novel risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral arterial circulations. It also appears to be a risk factor for venous thromboembolism. Low dietary intake of vitamins B₆ and folic acid is the most prevalent cause of hyperhomocyst(e)inemia. A critical unresolved question is whether hyperhomocyst(e)inemia itself, or alternatively some other effect of low vitamin levels, is the true determinant of excess cardiovascular risk. This issue is currently being addressed by prospective epidemiologic studies. There is also an urgent need for prospective randomized studies to determine whether vitamin supplementation is beneficial in the primary or secondary prophylaxis of atherosclerotic disease. In the meantime, lifestyle modifications and vitamin supplementation to reduce plasma homocysteine levels can be recommended, because these are innocuous interventions that may well prove to be beneficial. Until there is definitive evidence that treatment of hyperhomocyst(e)inemia does in fact alter clinical outcomes, however, other therapies that possess the potential for greater toxicity cannot be justified.     

Effect of hormone replacement therapy on plasma levels of the cardiovascular risk factor asymmetric dimethylarginine: a randomized,placebo-controlled 12-week study in healthy early postmenopausal women

In a prospective, randomized, placebo-controlled 12-wk study, we investigated the effect of oral hormone replacement therapy on asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), and an independent risk factor for coronary heart disease. The effects on arginine and symmetric dimethylarginine were also investigated. Sixty healthy early postmenopausal women received daily placebo (n = 16) or oral 17beta-estradiol 2 mg, either unopposed (E(2); n = 16) or sequentially combined with dydrogesterone 10 mg (E(2)+D; n = 14) or trimegestone 0.5 mg (E(2)+T; n = 14). ADMA levels reduced in all active treatment groups. Compared with baseline and placebo, the largest reduction in ADMA levels was observed in the E(2)+T group [-18.7% (95% confidence interval [CI], -25.4 to -11.9%) and -21.1% (95% CI, -26.2 to -16.1%), at 4 and 12 wk, respectively]. At 4 and 12 wk in the E(2)+T group, arginine levels were significantly reduced as well [-30.9% (95% CI, -41.1 to -20.7%) and -36.3% (95% CI, -43.1 to -29.5%), respectively], whereas symmetric dimethylarginine levels were significantly lower in the E(2)+D group after 12 wk [-11.6% (95% CI, -19.9 to -3.3%)]. In conclusion, unopposed oral estradiol and estradiol combined with dydrogesterone or trimegestone reduced plasma levels of the NOS inhibitor ADMA. Whether the reduction of the NOS substrate arginine in the E(2)+T group counteracts the potentially beneficial effect of ADMA reduction or reflects increased NO production remains to be investigated.     

Homocysteine as a risk factor for cardiovascular disease

Homocysteine is an amino acid that appears to damage the vascular endothelium and promote thrombosis. The most frequent causes of hyperhomocyst(e)inemia are the inherited defect of the enzyme cystathinonine B-synthase and nutritional deficiency of vitamin B(12) or folate. Hyperhomocyst(e)inemia is associated, perhaps causally, with atherosclerotic vascular disease. Interactions with risk factors such as cigarette smoking, hyperlipidemia, and hypertension are possible, but not yet defined. Dietary supplementation with vitamin B(12), folate, and other substances can reduce homocysteine levels. Such simple measures may reduce the risk of vascular disease in hyperhomocyst(e)inemic subjects.     

Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment

A high concentration of plasma asymmetric dimethylarginine (ADMA) has been associated with several risk factors for atherosclerosis, and this may increase the risk for acute coronary syndromes (ACSs). We measured plasma ADMA concentrations in patients who had newly diagnosed ACS (n = 48), and we followed the changes in ADMA concentrations during these patients' short-term medical therapy, which included various combination of drugs with or without percutaneous coronary interventions according to the needs of each patient. Concentrations of plasma ADMA were found to be high in patients who had ACS compared with 48 age-matched healthy control subjects (3.13 +/- 0.85 vs 1.57 +/- 0.85 mumol/L, p <0.0001). Follow-up measurements of ADMA showed dramatic decreases in plasma ADMA concentrations over 2 weeks of medical therapy for ACS (from 3.27 +/- 0.87 to 1.52 +/- 0.47 mumol/L, p <0.0001). Plasma ADMA at baseline showed a significant positive correlation with serum C-reactive protein and plasma insulin and a significant negative correlation with serum levels of high-density lipoprotein and plasma alpha-tocopherol. During therapy, changes in plasma ADMA concentrations were significantly correlated with changes in the ratio of total cholesterol to high-density lipoprotein cholesterol and in serum C-reactive protein concentrations but not with changes in insulin levels. This study provides the first evidence that plasma ADMA concentrations are significantly high in patients who have ACS and that ADMA concentrations rapidly decrease after short-term medical therapy.     

Homocysteine as a novel risk factor for atherosclerosis.

Homocysteine is a sulfhydryl amino acid formed during metabolism of methionine. Increasing evidence suggests that homocyst(e)ine may act as an independent risk factor for ischemic heart disease, cerebrovascular disease, and peripheral arterial disease. Recent prospective data have shown that homocyst(e)ine levels in the top 20% of the population increase the risk for ischemic heart disease by approximately twofold. Homocyst(e)ine seems to promote the progression of atherosclerosis by causing endothelial dysfunction, increasing oxidant stress, and promoting vascular smooth muscle growth. Recent human studies using methionine loading to experimentally induce moderate hyperhomocyst(e)inemia have demonstrated rapid and profound impairment of resistance and conduit artery endothelial function. No data are available from randomized, controlled trials of the effects of lowering plasma homocyst(e)ine on atherosclerotic vascular events; however, screening for hyperhomocyst(e)inemia should be actively considered in individuals with progressive and unexplained atherosclerosis. Both fasting and postmethionine load homocyst(e)ine levels should be measured. B vitamins, including folic acid and vitamins B6 and B12 are the mainstay of treatment of patients with hyperhomocyst(e)inemia. Primary prevention strategies await the completion of long-term, randomized, prospective studies.     

Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma

BACKGROUND AND AIMS: A low dietary folate intake can cause genomic DNA hypomethylation and may increase the risk of colorectal neoplasia. The hypothesis that folic acid supplementation increases DNA methylation in leucocytes and colorectal mucosa was tested in 31 patients with histologically confirmed colorectal adenoma using a randomised, double blind, placebo controlled, parallel design. METHODS: Subjects were randomised to receive either 400 microg/day folic acid supplement (n = 15) or placebo (n = 16) for 10 weeks. Genomic DNA methylation, serum and erythrocyte folate, and plasma homocysteine concentrations were measured at baseline and post intervention. RESULTS: Folic acid supplementation increased serum and erythrocyte folate concentrations by 81% (95% confidence interval (CI) 57-104%; p<0.001 v placebo) and 57% (95% CI 40-74%; p<0.001 v placebo), respectively, and decreased plasma homocysteine concentration by 12% (95% CI 4-20%; p = 0.01 v placebo). Folic acid supplementation resulted in increases in DNA methylation of 31% (95% CI 16-47%; p = 0.05 v placebo) in leucocytes and 25% (95% CI 11-39%; p = 0.09 v placebo) in colonic mucosa. CONCLUSIONS: These results suggest that DNA hypomethylation can be reversed by physiological intakes of folic acid.     

The role of vitamins in the pathogenesis and treatment of hyperhomocyst(e)inaemia

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.     

Effect of lowering of homocysteine levels on inflammatory markers: a randomized controlled trial

BACKGROUND: Elevated concentrations of homocysteine and low concentrations of folate may lead to a proinflammatory state that could explain their relation to vascular disease risk. We investigated the effect of lowering homocysteine concentrations by means of folic acid supplementation on markers of inflammation. METHODS: In a double-blind, randomized, placebo-controlled trial among 530 men and postmenopausal women with homocysteine concentrations of 1.8 mg/L or higher (>/=13 micromol/L) at screening, we investigated the effect of folic acid supplementation (0.8 mg/d) vs placebo for 1 year on serum concentrations of C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein. RESULTS: After 1 year of supplementation, concentrations of serum folate increased by 400% (95% confidence interval [CI], 362%-436%), and those of homocysteine decreased by 28% (95% CI, 24%-36%) in the folic acid group compared with the placebo group. However, no changes in plasma concentrations of the inflammatory markers were observed. CONCLUSIONS: Although homocysteine is associated with vascular disease risk in the general population, marked lowering of slightly elevated homocysteine concentrations by means of 1-year folic acid supplementation does not influence inflammatory responses involving C-reactive protein, soluble intercellular adhesion molecule-1, oxidized low-density lipoprotein, and autoantibodies against oxidized low-density lipoprotein.     

No effect of B vitamins on ADMA levels in patients at increased cardiovascular risk

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is a recently identified potent cardiovascular risk factor. ADMA levels are increased in hyperhomocysteinaemia and the metabolism of ADMA is linked with that of homocysteine in several ways. Treatment with B vitamins effectively reduces homocysteine levels, but studies investigating the effect on ADMA levels are scarce and show conflicting results. In this study we evaluated the effect of treatment with B vitamins on ADMA levels in two high cardiovascular risk populations. METHODS: In study I, 110 siblings of patients with clinical atherosclerotic disease and postmethionine hyperhomocysteinaemia were treated with 5 mg of folic acid and 250 mg of pyridoxine or placebo, and were analysed after 1 year. In study II, 41 patients with type 2 diabetes and mild hyperhomocysteinaemia were analysed after 6 months treatment with 5 mg of folic acid or placebo. RESULTS: A correlation between baseline homocysteine and ADMA levels was found, which was partly due to confounding by renal function. Homocysteine levels decreased by 43% in study I and by 28% in study II. In both studies, treatment with B vitamins had no effect at all on ADMA, arginine/ADMA ratio and SDMA levels. This result was confirmed in multiple linear regression analyses with adjustment for baseline values and gender. CONCLUSIONS: Our studies indicate that B vitamins, despite causing a substantial reduction in plasma homocysteine levels, have no beneficial effect on ADMA levels.     

Hydroxocobalamin reduces hyperhomocysteinemia in end-stage renal disease

Renal failure causes hyperhomocysteinemia, an important risk factor for cardiovascular disease and venous access thrombosis in end-stage renal disease (ESRD). Folic acid is necessary for homocysteine (Hcy) metabolism, and therapy with 1 mg/d or more of folic acid reduces plasma total Hcy (tHcy) concentrations in ESRD, although seldom to normal. In contrast to folic acid, the Hcy-lowering effect of vitamin B(12) has not been well studied in ESRD. We performed a prospective randomized controlled clinical trial involving 24 maintenance hemodialysis patients with normal or supranormal serum folate and vitamin B(12) concentrations who received either standard therapy, which included 5 to 6 mg folic acid, 5 to 10 mg pyridoxine, and 6 to 10 microg oral vitamin B(12) per day, or standard therapy plus 1 mg hydroxocobalamin administered subcutaneously once per week after dialysis. Plasma tHcy and serum methylmalonic acid (MMA) concentrations were measured before and after 8 and 16 weeks of continuous treatment. Hydroxocobalamin reduced plasma tHcy by an average of 32% (P <.005) and serum MMA by an average of 19% (P <.001). The Hcy-lowering effect of hydroxocobalamin was independent of baseline serum vitamin B(12), folic acid, and MMA concentrations. Patients with higher baseline plasma tHcy concentrations had the greatest response (r = 0.80; P <.002). These results show that parenteral hydroxocobalamin reduces plasma tHcy dramatically in vitamin B(12)-replete hemodialysis patients. Persons with considerable persisting hyperhomocysteinemia despite high-dose folic acid therapy are likely to respond to the addition of hydroxocobalamin, irrespective of their serum vitamin B(12) concentrations.     

Effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease

OBJECTIVES: The purpose of this study was to determine whether lowering homocysteine levels with folic acid, with or without antioxidants, will improve endothelial dysfunction in patients with coronary artery disease (CAD). BACKGROUND: Elevated plasma homocysteine levels are a risk factor for atherosclerosis. Homocysteine may promote atherogenesis through endothelial dysfunction and oxidative stress. METHODS: In a double-blind, placebo-controlled, randomized trial, we used vascular ultrasound to assess the effect of folic acid alone or with antioxidants on brachial artery endothelium-dependent flow-mediated dilation (FMD). Seventy-five patients with CAD (screening homocysteine level > or =9 micromol/liter) were randomized equally to one of three groups: placebo, folic acid alone or folic acid plus antioxidant vitamins C and E. Patients were treated for four months. Plasma folate, homocysteine, FMD and nitroglycerin-mediated dilation were measured before and after four months of treatment. RESULTS: Plasma folate, homocysteine and FMD were unchanged in the placebo group. Compared with placebo, folic acid alone increased plasma folate by 475% (p < 0.001), reduced plasma homocysteine by 11% (p = 0.23) and significantly improved FMD from 3.2 +/- 3.6% to 5.2 +/- 3.9% (p = 0.04). The improvement in FMD correlated with the reduction in homocysteine (r = 0.5, p = 0.01). Folic acid plus antioxidants increased plasma folate by 438% (p < 0.001), reduced plasma homocysteine by 9% (p = 0.56) and insignificantly improved FMD from 2.6 +/- 2.4% to 4.0 +/- 3.7% (p = 0.45), as compared with placebo. Nitroglycerin-mediated dilation did not change significantly in any group. CONCLUSIONS: Folic acid supplementation significantly improved endothelial dysfunction in patients with coronary atherosclerosis. Further clinical trials are required to determine whether folic acid supplementation may reduce cardiovascular events.     

Asymmetric dimethyl arginine levels correlate with cardiovascular risk factors in patients with erectile dysfunction

BACKGROUND: Erectile dysfunction is related to penile arterial endothelial nitric oxide production. Asymmetric dimethylarginine (ADMA) and E-selectin are often considered plasma markers of endothelial function. OBJECTIVE: This study investigated the relationship between these plasma markers and cardiovascular risk factors in patients with erectile dysfunction. METHODS AND RESULTS: Cardiovascular risk factors, ADMA and E-selectin were assessed in 45 patients with erectile dysfunction. Plasma markers showed associations with baseline risk factors. E-selectin levels showed an inverse relationship with age (p = 0.005) and statin therapy (p = 0.03) and a weak association with concomitant beta-blocker therapy (p = 0.05). Compared to these relatively weak associations with cardiovascular risk factors, ADMA levels showed strong associations with pulse pressure (p < 0.001), lack of smoking (p = 0.002) and lipoprotein (a) (p = 0.004) concentrations and weak associations with LDL-cholesterol (p = 0.02), and C-reactive protein levels (p = 0.04). ADMA levels correlated with E-selectin (partial r = 0.76; p < 0.001) after adjustment for lipoprotein (a), pulse pressure and smoking. No change in E-selectin or ADMA levels was seen after 70 days therapy with sildenafil and no relationship was found between either plasma marker and the acute pulse wave response to a single challenge dose of sildenafil. CONCLUSION: ADMA levels correlate at baseline with some cardiovascular risk factors including inflammatory markers and lipoprotein (a) in patients with erectile dysfunction.     

Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA

Hyperhomocysteinemia is associated with an enhanced risk for cardiovascular disease. Patients with peripheral arterial disease (PAD) show an increased prevalence of hyperhomocysteinemia. A decreased biological activity of nitric oxide (NO) may contribute to homocysteine-associated endothelial dysfunction. This study was designed to investigate whether elevated levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are involved in endothelial dysfunction in patients with chronic hyperhomocysteinemia and PAD. A total of 76 patients (58 males and 18 females; mean age 65.2 +/- 2.0 years) with PAD were included in the analysis and characterized according to demographic variables and cardiovascular risk factors. Flow-dependent vasodilation (FDD) was determined by high-resolution ultrasound in the radial artery. Total plasma homocysteine (plasma tHcy) and ADMA levels were measured by HPLC. Urinary nitrate was quantified using gas chromatography-mass spectrometry. Patients with plasma tHcy in the highest tertile (n = 27; i.e. > 10.6 micromol/l) had a mean plasma level of 14.4 +/- 1.21 mol/l compared with 9.9 +/- 0.1 micromol/l in those patients in the middle tertile (n = 22; p < 0.05) and 9.4 +/- 0.1 micromol/l in those in the lowest tertile (n = 27; i.e. <9.6 micromol/l; p < 0.05). The hyperhomocysteinemic individuals (highest tertile) had a significantly decreased FDD compared with healthy age-matched controls (n = 15) (7.6 +/- 1.0 vs 13.0 +/- 0.4%; p < 0.05), higher plasma ADMA concentrations (4.0 +/- 0.3 vs 2.6 +/- 0.3 micromol/l; p < 0.05), and a lower urinary nitrate excretion rate (89.5 +/- 13.4 vs 131.3 +/- 17.9 micromol/mmol creatinine; p < 0.05) compared with patients with plasma tHcy in the lowest tertile. Multivariate regression analysis including plasma tHcy, ADMA, total cholesterol, diabetes mellitus, smoking, and systolic blood pressure revealed ADMA as the only significant factor determining FDD (p < 0.05). In conclusion, we demonstrated a stronger relationship between impaired endothelial function and elevated ADMA levels in comparison with plasma tHcy concentrations in patients with PAD and chronic hyperhomocysteinemia. This may raise the question of whether different therapeutical options that interact indirectly with plasma tHcy, i.e. treatment with ACE inhibitors and AT1-receptor blockers to reduce ADMA plasma concentrations or L-arginine, could be a beneficial tool for treating patients with hyperhomocysteinemia.     

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

In the present work we measured blood levels of total homocysteine (_tHcy), vitamin B₁₂ and folic acid in patients with Parkinson′s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma _tHcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of _tHcy in PD patients was folic acid deficiency, whereas in controls _tHcy levels were mainly determined by plasma vitamin B₁₂ concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma _tHcy, folic acid and vitamin B₁₂ levels in parkinsonians. Furthermore, disease duration was positively associated with _tHcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder.     

Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence.

PURPOSE: To review epidemiologic studies on the association between homocyst(e)ine level and risk for cardiovascular disease and the potential benefits of homocysteine-decreasing therapies. DATA SOURCES: Computerized and manual searches of the literature on total homocysteine levels and cardiovascular disease. STUDY SELECTION: Prospective studies and major retrospective epidemiologic studies evaluating the association between homocyst(e)ine levels and cardiovascular disease and the association between blood levels or dietary intake of folate, vitamin B6, and vitamin B12 and cardiovascular disease. DATA EXTRACTION: Relevant data on patient population, plasma homocyst(e)ine levels, duration of follow-up, and main results were extracted from studies that met the inclusion criteria. DATA SYNTHESIS: The designs and results of studies included in this review are summarized. A formal meta-analysis was not performed because the studies were heterogeneous in method and design. CONCLUSIONS: Results of epidemiologic studies suggest that moderately elevated plasma or serum homocyst(e)ine levels are prevalent in the general population and are associated with an increased risk for cardiovascular disease, independent of classic cardiovascular risk factors. Simple, inexpensive, nontoxic therapy with folic acid, vitamin B6, and vitamin B12 reduces plasma homocyst(e)ine levels. Although the association between homocyst(e)ine levels and cardiovascular disease is generally strong and biologically plausible, the data from the prospective studies are less consistent. In addition, epidemiologic observations of an association between hyperhomocyst(e)inemia and cardiovascular risk do not prove the existence of a causal relation. Therefore, the effectiveness of folate, vitamin B6, and vitamin B12 in reducing cardiovascular morbidity and mortality requires rigorous testing in randomized clinical trials. Several such trials are under way; their results may greatly affect cardiovascular morbidity and mortality, given the simplicity and low cost of vitamin therapy.     

Pathogenicity of thermolabile methylenetetrahydrofolate reductase for vascular dementia

Although the major biochemical abnormality due to methylenetetrahydrofolate reductase (MTHFR) deficiency is hyperhomocyst(e)inemia, its pathogenicity appears to involve more than homocysteine toxicity. In patients with severe MTHFR deficiency, a metabolite(s) other than hyperhomocyst(e)inemia also appears to be associated with its clinical manifestation in cerebrovascular disease. To elucidate the specific role of the TT genotype of MTHFR in the development of cerebral infarction with and without cognitive impairment, we determined the prevalence of hyperhomocyst(e)inemia and the C677T genotypes of MTHFR in 143 patients with vascular dementia, 122 patients with cerebral infarction, and 217 healthy subjects matched for age and sex. Prevalence of hyperhomocyst(e)inemia [homocyst(e)ine >/=15 micromol/L] was higher in cerebrovascular patients with or without dementia than in normal control subjects (42.6%, 20.5%, and 10.1%, respectively; P=0.001). In contrast, a higher frequency of MTHFR TT genotype was found only in demented patients compared with nondemented patients and healthy controls (25.2%, 9.8%, and 12.0%, respectively; P=0.01). When the study subjects were divided into normohomocyst(e)inemic and hyperhomocyst(e)inemic groups, the TT genotype was significantly associated with the risk for vascular dementia in the hyperhomocyst(e)inemic group (odds ratio 4.13, 95% CI 2.18 to 7.85; P=0.03) but not in the normohomocyst(e)inemic group. Demented patients with multiple infarcts had a higher frequency of TT genotype (odds ratio 3.13, 95% CI 2.23 to 4.39; P=0.0007), whereas those with a single infarct did not (odds ratio 2.03, P=0.15). In contrast, there was no significant association of the TT genotype with multiple infarcts in hyperhomocyst(e)inemic stroke patients. Taken together, these findings indicate a possible role of MTHFR TT genotype combined with hyperhomocyst(e)inemia in the pathogenesis of vascular dementia. Similar to the relationship between homocystinuria due to severe MTHFR deficiency and severe cystathionine beta-synthase deficiency, the TT genotype of MTHFR in hyperhomocyst(e)inemic subjects is differentiated from the cases of the TT genotype without hyperhomocyst(e)inemia or hyperhomocyst(e)inemia without the TT genotype in the development of cerebrovascular disease.