Higher Homocysteine Concentrations Research Articles

Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.

802-5 High Homocysteine Concentrations: An Independent Risk Factor for Coronary Atherosclerosis in Women

High plasma homocysteine concentration is a significant risk factor for premature vascular disease in men, but the role in determining coronary disease risk in women remains unclear. Risk factors, including hypertension, hypercholesterolemia, smoking, and diabetes were recorded in 228 patients (175 men, 53 women) with angiographically documented coronary disease (≥70% stenosis of at least one major coronary vessel), and 223 healthy controls (181 men, 42 women), Fasting total plasma homocysteine was measured in all subjects. A high homocysteine concentrations was defined as a level greater than the 80th percentile, adjusted for gender. In univariate analysis, homocysteine correlated with age, but not smoking, hypertension or hypercholesterolemia. Homocysteine values and odds ratios based upon multivariate analysis were: Women Men Patients Controls Patients Controls Age 62 ± 12 * 53 ± 10 61 ± 11 * 51 ± 10 Homocysteine Level( μ mol/L) 127 ± 4.4 * 102 ± 4.9 13.1 ± 4.3 * 11.3 ± 30 Percent High Homocysteine 55 * , † 20 35 * 20 Odds Ratio 3.2 * NA 1.9 * NA Confidence Interval 1.2-8.4 NA 11-33 NA * p &lt; 0.01 vs controls † p &lt; 0.05 vs male patients Mean homocysteine concentrations are higher in women with coronary disease than age and sex matched controls. High homocysteine levels are more frequently seen in women than men and confer an independent three-fold incremental risk of CAD.

1015-72 Elevated Plasma Homocysteine: An Important Independent Risk Factor for Coronary Artery Disease in the Elderly

High plasma homocysteine (HCY) concentration is an established risk factor for premature vascular disease which can be reduced using vitamin therapy. The role of increased homocysteine as a coronary risk factor in the elderly, however, remains uncertain. We studied 228 patients with angiographically documented coronary disease (≥ 70% stenosis in at least one major epicardial vessel). These included 136 patients less than, and 92 greater than 65 years old. Patients were compared to 223 healthy controls 199 (&lt;65) and 24 (&gt; 65). The presence of traditional risk factors including hypertension, smoking, hypercholesterolemia and diabetes mellitus were noted. Total fasting plasma homocysteine was measured in all subjects. A gender-adjusted threshold for a high homocysteine level was defined as the 80th percentile for healthy controls (corresponding to a level of 11.7 μ mol/L in women and 13.6 μ mo1/L in men). Age &lt; 65 Age &gt; 65 Patients Controls Patients Controls Homocysteine 12.2 ± 4.0 * 11.0 ± 3.4 14.2 ± 4.6 * 11.9 ± 3.6 High HCY(%) 33 * 20 50 † 25 Odds Ratios 2.0 * NA 2.9 * NA Confidence Interval 1.2–3.2 NA 1.0–8.3 NA * p &lt; am vs controls † p &lt; 0.03 Homocysteine concentrations are elevated in patients with coronary artery disease older than 65 years in age. A high value confers an independent three-fold risk for coronary disease in this patient group. Accordingly, intervention studies designed to reduce plasma homocysteine levels should not exclude the elderly.

Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women.

In a prospective study we investigated the possible changes in fasting serum total homocysteine concentrations during continuous micronized 17 beta-oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, 10 mg daily during the first 14 days of each 28 day cycle, in 21 healthy non-hysterectomized postmenopausal women. During the first six cycles mean serum homocysteine decreased by 10.9% (P = 0.013), after which no further significant changes were found during the 2 years of treatment. A 16.9% decrease (P = 0.017; n = 8) was found in women with high homocysteine concentrations, while in women with low homocysteine concentrations (n = 13) no significant changes were observed. The observed decrease in high homocysteine concentrations in postmenopausal women may in part contribute to the decreased risk of developing cardiovascular disease during hormone replacement therapy.

Homocysteine and coronary artery disease.

Homocystinuria is a rare autosomal recessive disease complicated by early and aggressive occlusive arterial disease. This may be related to the grossly increased homocysteine concentrations seen in this disease. More recently, milder hyperhomocysteinemia has been proposed as an independent risk factor for coronary artery disease. Many patients with homozygous homocystinuria develop severe premature atherosclerosis and thromboembolism, probably caused by abnormally high concentrations of homocysteine. Homocysteine undergoes metabolism either by remethylation or transsulfuration, and deficiency or dysfunction of any of the substances that regulate these reactions may lead to hyperhomocysteinemia. Homocysteine may have adverse effects on platelets, clotting factors, and endothelial cells. Studies have demonstrated significantly higher plasma homocysteine levels in patients with occlusive arterial disease than in controls. The causes are not clearly understood but may include deficiency of vitamin B6, vitamin B12, and folic acid and heterozygosity for cystathionine synthase deficiency. Vitamin supplementation can lower plasma homocysteine levels. Whether measuring plasma homocysteine levels in patients with coronary artery disease should be routine and whether treating hyperhomocysteinemia in these patients may reduce the risk of coronary events remains to be determined.

Homocysteine Increases as Folate Decreases in Plasma of Healthy Men during Short-Term Dietary Folate and Methyl Group Restriction

Ten healthy adult men were fed a diet low in folate and exogenous methyl groups to study the effects on folate requirement and status. The men were housed in a metabolic unit for the entire 108-d study. After a 9-d base-line period (P1), the men were fed an amino acid-defined soybean product diet for 45 d, which provided 25 micrograms/d of folate for 30 d (P2) and (with a folate supplement) 99 micrograms/d for 15 d (P3). During P2 and P3, the low methionine and choline diet was supplemented with methionine for half the subjects to vary the dietary methyl group intake. The periods were then repeated over the next 54 d (P4-P6), with a cross-over of methionine intakes in P5 and P6. Restricting dietary methyl group intake did not increase the dietary folate requirement. Plasma total homocysteine rose during folate depletion and correlated inversely with plasma folate; however, the response of homocysteine to changes in folate intake varied among individuals from very strong to absent. The results support previous suggestions that increased plasma homocysteine concentrations provide a marker of functional folate deficiency, and further indicate that individuals may differ greatly in their susceptibility to hyperhomocysteinemia due to low folate intakes. Judged by the lack of normalization of high homocysteine concentrations during folate repletion, the current folate RDA for adult men may not provide the expected margin of protection.

Study on the presence of homocysteine in ovarian follicular fluid

To study the presence of homocysteine, methionine and the vitamins folate, B 12 , and B 6 in human ovarian follicular fluid (FF). Measurement of homocysteine, methionine, folate, and vitamins B 12 and B 6 in ovarian FF and blood. Academic Department of Obstetrics and Gynecology at St. Radboud Hospital, Nijmegen, The Netherlands. Fourteen healthy women undergoing an IVF program. Detectable amounts of homocysteine and methionine were found in FF. Homocysteine concentrations were similar to those in serum. Methionine concentrations proved to be slightly but significantly lower than in corresponding serum samples. Concentrations of vitamins B 12 and B 6 were significantly lower in FF than in serum, whereas folate concentrations were not significantly different. A statistically significant correlation between corresponding serum and FF concentrations of homocysteine, folate, and vitamin B 12 could be established. These data support the hypothesis that the ovum might be exposed to high homocysteine or low methionine concentrations, or both, and a lack of vitamins, which might be important in fertilization and early embryogenesis.

Human arterial endothelial cell detachment in vitro: its promotion by homocysteine and cysteine

We have explored earlier evidence that premature atherosclerosis in homocystinuria is triggered by homocysteine-induced loss of vascular endothelium. We used a reproducible sluicing assay to test in vitro detachment of human arterial endothelial cells. Cell detachment was induced by exposure of cultured endothelial cells to the sulphydryl-containing amino acids homocysteine and cysteine, whereas methionine, alanine, valine and isoleucine at comparable concentrations were ineffective. This cellular detachment was greatly diminished by growth of the endothelial cells on fibronectin coated- rather than plain tissue culture dishes. Considerably higher concentrations of homocysteine were required for in vitro effects than are associated with atherogenesis in homocystinuria, and despite the cysteine associated changes, cysteine itself is not known to be related to atherogenesis. These data suggested that in vitro detachment of cultured endothelial cells, induced by sulphydryl-containing amino acids, may have marginal relevance to mechanisms of atherogenesis in homocystinuria.

Plasma Homocysteine in Venous Thromboembolism

Severe hyperhomocysteinemia due to inborn errors of methionine metabolism results in precocious development of arteriosclerosis and predisposition to venous and arterial thromboembolism. Although the findings of several studies have indicated that mild hyperhomocysteinemia is common in occlusive arterial disease, no similar studies have been made on venous thromboembolism. In this study of subjects under 50 years of age, we found no significant differences in the plasma homocysteine concentrations, either in the fasting state or after methionine loading, between 42 patients with venous thromboembolism and 42 healthy controls. Nonetheless, male patients manifested a tendency toward higher homocysteine concentrations than male controls; 6 patients (14%) versus 2 controls (5%) responded abnormally to methionine loading which might indicate heterozygosity for cystathionine synthase deficiency. Thus, further studies on plasma homocysteine in venous thromboembolism are warranted.

Vitamin B&lt;sub&gt;12&lt;/sub&gt; Analogues, Homocysteine, Methylmalonic Acid, and Transcobalamins in the Study of Vitamin B&lt;sub&gt;12&lt;/sub&gt; Deficiency in Primary Degenerative Dementia

B&lt;sub&gt;12&lt;/sub&gt; analogues, homocysteine, methylmalonic acid (MMA), and unsaturated transcobalamins, all potential markers of vitamin B&lt;sub&gt;12&lt;/sub&gt; status, were analyzed in blood and cerebrospinal fluid (CSF) from 22 patients with primary degenerative dementia of Alzheimer type. The level of active vitamin B12 in serum correlated significantly with serum homocysteine, serum MMA, and CSF homocysteine. CSF B&lt;sub&gt;12&lt;/sub&gt; correlated significantly with serum homocysteine and serum MMA. The ratio of analogues and active vitamin B&lt;sub&gt;12&lt;/sub&gt; concentrations in serum (analogue/active B&lt;sub&gt;12&lt;/sub&gt; ratio) correlated significantly with serum homocysteine, serum MMA and CSF B&lt;sub&gt;12&lt;/sub&gt;. This study had no control group. However, based on available reference values, high concentrations of homocysteine and MMA in serum and unsaturated transcobalamin II in plasma were interpreted as evidence of vitamin B&lt;sub&gt;12&lt;/sub&gt; depletion or deficiency. Such high concentrations were found in a significant number of patients. In 9 patients, vitamin B&lt;sub&gt;12&lt;/sub&gt; injections were administered. After treatment, serum homocysteine levels fell significantly. We conclude that vitamin B&lt;sub&gt;12&lt;/sub&gt; analogues, homocysteine, MMA, and transcobalamins may be useful as markers in studies aimed at clarifying the role of vitamin B12 deficiency in dementia disorders.

Inborn Errors of Metabolism Causing Homocysteinemia and Related Vascular Involvement

Sulfur amino acids have been implicated in the pathogenesis of thromboembolic vascular disease, and observations of patients with several inborn errors of metabolism have led to the 'homocysteine theory of arteriosclerosis'. Homocysteine is an intermediate in the transsulfuration pathway and it enters into several other reactions, some of which involve transfer of methyl groups. An abnormally high concentration of homocysteine in the blood causes homocystinuria. Deficiency of cystathionine beta-synthase is the most frequent cause of homocystinuria. Patients with this disorder are at risk for early vascular occlusions. Treatment with vitamin B6 of patients who are biochemically responsive to this vitamin reduces the risk of thromboembolism. Clinical or pathologic evidence of early vascular disease has also been provided in patients with homocysteinemia due to deficient (re)methylation of homocysteine to methionine. This may be caused by a deficiency of 5,10-methylenetetrahydrofolate reductase or by a deficient synthesis of cobalamins.

Homocysteine content of plasma proteins in ischemic heart disease

It has been shown previously that accumulation of homocysteine produces atheromatous changes. The present study was done on 26 male survivors of myocardial infarction 2–3 months after the acute phase and 26 healthy males of the same age (30–60 years). The concentrations of homocysteine, its derivatives and other amino acids were determined in acid hydrolyzate of plasma and in deproteinized plasma. The plasma proteins of survivors of myocardial infarction were found to contain a high concentration of homocysteine. The average value was 958 ± 84 μmol/l of plasma, which was about 25 times the quantity found in the control group. Large differences were also found in α-amino adipic acid and cystathionine concentrations. These substances were found in significantly higher concentrations in the plasma of the survivors compared to controls. The high positive correlation between homocysteine and α-amino adipic acid level ( r = 0.83; P < 0.001) suggests a common source of these 2 compounds in the analyzed samples. The levels of the other 15 measured amino acids were not significantly different in the 2 groups. The results support the homocysteine theory and suggest a method for more exact diagnosis of atherosclerosis.

The effect of local application of homocysteine on neuronal activity in the central nervous system of the rat

Homocysteine, a monocarboxylic, sulfur-containing amino acid, produces convulsions in rats and mice when administered systemically. Convulsions and high serum concentrations of homocysteine are among the symptoms that characterize patients with homocystinuria, a hereditary disorder of amino acid metabolism. In order to evaluate the effects of homocysteine on the central nervous system directly, extracellular recordings were made from neurons in rat cerebral cortex, cerebellum and midbrain during local application of homocysteine by pressure ejection or iontophoresis. Both methods of drug delivery produced dose-dependent increases in the activity of neurons in every area tested. Activity was increased by D, L-homocysteine and L-glutamate in 67 percent of cells tested with both drugs. The doses required to produce equivalent excitations in this group of cells were similar, suggesting that homocysteine is at least as potent as glutamate. The excitatory effects of both homocysteine and glutamate were antagonized by local application of betaine, a biological methyl donor which blocks convulsions produced by systematic administration of pentylenetetrazol and electroshock as well as homocysteine. The effects of local application of homocysteine were also blocked by local application of the glutamate antagonist glutamate diethylester (GDEE). In 6 of 7 cells tested, GDEE appeared to preferentially affect homocysteine-induced excitations. These data indicate that homocysteine has an excitatory action on neurons, a finding which may account for some of the symptoms associated with certain disorders of amino acid metabolism.