Mechanisms of Venous and Arterial Thrombosis in Heparin-Induced Thrombocytopenia

This pictorial introduction to homocysteine illustrates at a glance the nature of homocysteine and its role in cardiovascular disease by means of eight simple figures and an essential bibliography. Homocysteine is a sulfur-containing metabolite of methionine. Conversion back to methionine or transsulfuration to cysteine are the two major metabolic pathways that reduce total homocysteine (tHcy) concentrations in cells and blood. B vitamins are essential cofactors in homocysteine metabolism. Median fasting total homocysteine levels in adult males are 10 µmol/L. Increased plasma tHcy concentrations are found with methionine-rich diets, low vitamin B intake, male gender, age, impaired renal function, and genetically determined defects of the enzymes involved in homocysteine metabolism. An inverse relation exists between plasma tHcy and circulating folate or vitamin B₆ concentrations, and folic acid supplements of 0.5 mg/d can reduce tHcy levels by 25%. Homocystinuric patients, who have severe hyperhomocysteinemia, die prematurely of atherothrombotic disease. Many (but not all) cross-sectional and prospective studies indicate, on average, that plasma tHcy levels <.10 µmol/L are associated with, or predict the development of, coronary, cerebral, and peripheral vascular disease. The risk conferred by hyperhomocysteinemia is graded and is independent of traditional risk factors, with an estimated odds ratio for ischemic heart disease of 1.4 for every 5 µmol/L increase in plasma tHcy. In vitro and in vivo, tHcy has been found to impair endothelial function. It is now well established that tHcy represents a marker of current or subsequent ischemic vascular disease. However, irrefutable proof that hyperhomocysteinemia actually causes atherothrombosis will come only if interventions to lower plasma tHcy will produce concomitant reductions in cardiovascular events.     

同型半胱氨酸对KKAy小鼠心肌病变的影响

目的　观察高同型半胱氨酸 (Hcy)血症对糖尿病小鼠心肌的影响 ,以及补充叶酸对心肌病变的作用。方法　2 4只KKAy小鼠随机分成 3组 ,分别喂养高热量饮食 (KA组 )、高蛋氨酸饮食 (KB组 )以及高蛋氨酸加叶酸、维生素B1 2 饮食 (KC组 )。测定各组血浆Hcy、叶酸、维生素B1 2 水平 ,并观察心肌病理改变。结果　饲养 16周后 ,KB组血浆Hcy明显增高 [(2 9.33± 16 .85对 5 .33± 2 .0 3) μmol L ,P <0 .0 0 1],且心肌间质纤维化、钙化、小动脉管壁增厚、透明变性等病变加重 ,经叶酸、维生素B1 2 治疗的KC组血浆Hcy降至正常 (4 .0 4± 1.81) μmol L ,且心肌病变减轻。结论Hcy可以加重糖尿病小鼠的心肌病变 ,叶酸、维生素B1 2 可以有效减缓这一病变进程。     

Effects of betaine in a murine model of mild cystathionine-beta-synthase deficiency

Cystathionine-β-synthase (CBS) is required for transsulfuration of homocysteine, an amino acid implicated in vascular disease. We studied homocysteine metabolism in mice with mild hyperhomocysteinemia due to a heterozygous disruption of the Cbs gene. Mice were fed diets supplemented with betaine or dimethylsulfonioacetate (DMSA); betaine and DMSA provide methyl groups for an alternate pathway of homocysteine metabolism, remethylation by betaine:homocysteine methyltransferase (BHMT). On control diets, heterozygous mice had 50% higher plasma homocysteine than did wild-type mice. Betaine and DMSA had similar effects in both genotype groups: liver betaine increased dramatically, while plasma homocysteine decreased by 40% to 50%. With increasing betaine supplementation, homocysteine decreased by 75%. Plasma homocysteine and BHMT activity both showed a strong negative correlation with liver betaine. Homocysteinemia in mice is sensitive to a disruption of Cbs and to methyl donor intake. Because betaine leads to a greater flux through BHMT and lowers homocysteine, betaine supplementation may be beneficial in mild hyperhomocysteinemia.     

Effects of vitamin supplementation and hyperhomocysteinemia on atherosclerosis in apoE-deficient mice

It has been demonstrated that hyperhomocysteinemia (HHcy) accelerates atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. In this study, vitamin-defined chow diets were used to induce HHcy in apoE(-/-) mice in an attempt to identify possible pathogenic pathways. Six-week-old female apoE(-/-) mice were divided into seven groups: vitamin-defined purified chow diet alone (control), or same diet supplemented with either D,L-homocysteine (upward arrow Hcy) or L-homocystine (upward arrow Hcy-Hcy), or diet high in L-methionine (upward arrow Met), or diet high in B-vitamins (upward arrow vitamin), or diets deficient in folate (downward arrow folate) or vitamin B(6) ( downward arrow B(6)). Eighteen weeks later, plasma total homocysteine (tHcy), lipids and atherosclerotic plaque burden (aortic root, aortic arch, and brachiocephalic trunk) were measured. tHcy levels were similar in the upward arrow vitamin, downward arrow folate, downward arrow B(6) and control groups (9.2-10.1 micromol/l, NS), but elevated mildly in the upward arrow Hcy-Hcy group (16.1 micromol/l) and moderately in the upward arrow Met and upward arrow Hcy groups (53.6 and 51.5 micromol/l, respectively). Mice in the latter two groups had significantly more atherosclerosis in the aortic root. Although B vitamin-supplementation failed to lower tHcy levels, mice had less atherosclerosis in the aortic arch. In summary, dietary methionine and homocysteine, but not homocystine, enhanced the development of atherosclerosis. Supplementation with B vitamins appeared to confer homocysteine-independent protection against atherosclerosis. These results suggest that (1) there may be a threshold level below which homocysteine is not atherogenic; (2) the atherogenic effect of HHcy may be mediated via an intracellular pathway; and/or (3) the anti-atherogenic effect of B vitamins in normohomocysteinemic mice is independent of tHcy levels.     

Diet-induced mild hyperhomocysteinemia and increased salt intake diminish vascular endothelial function in a synergistic manner.

OBJECTIVES: We investigated the influence of hyperhomocysteinemia and high salt intake on sodium handling, oxidative state, vascular endothelial function and blood pressure in a rat model. METHODS: Eight-week-old male Sprague-Dawley rats were divided into subgroups and maintained for 4 weeks prior to experimentation on either control chow containing 0.36% methionine and 0.5% NaCl; or one of the following modified diets containing either 0.7% methionine, 8% NaCl or 0.7% methionine + 8% NaCl. Sodium handling, homocysteine metabolism, lipid profile, NO synthesis, oxidative state, blood pressure and relaxation to acetylcholine of carotid rings were evaluated and compared. RESULTS: Diet-induced mild hyperhomocysteinemia (plasma homocysteine levels 1.4-fold higher than control), by itself, had no significant influence on sodium excretion, vascular endothelial function and blood pressure. Increased salt intake had no influence on homocysteine metabolism, vascular endothelial function and blood pressure. The coexistence of mild hyperhomocysteinemia and high salt intake significantly diminished vascular endothelial function (rmax to acetylcholine; control chow 83.2 +/- 6.2%, 0.7% methionine diet 74.7 +/- 3.9%, 8% NaCl diet 85.1 +/- 4.6%, 0.7% methionine + 8% NaCl diet 57.9 +/- 6.6%) but manifested no rise in blood pressure. No significant difference in oxidative state was observed in this analysis. CONCLUSIONS: Diet-induced mild hyperhomocysteinemia, the extent of which is comparable with the levels that are associated with a predisposition to common atherosclerotic diseases, was found to induce vascular endothelial dysfunction only when accompanied by high salt intake.     

Clinical use and rational management of homocysteine, folic acid, and B vitamins in cardiovascular and thrombotic diseases

About half of all deaths are due to cardiovascular disease and its complications. The economic burden on society and the healthcare system from cardiovascular disability, complications, and treatments is huge and becoming larger in the rapidly aging populations of developed countries. As conventional risk factors fail to account for part of the cases, homocysteine, a "new" risk factor, is being viewed with mounting interest.Homocysteine is a sulfur-containing intermediate product in the normal metabolism of methionine, an essential amino acid. Folic acid, vitamin B(12), and vitamin B(6) deficiency and reduced enzyme activities inhibit the breakdown of homocysteine, thus increasing the intracellular homocysteine concentration. Numerous retrospective and prospective studies have consistently found an independent relationship between mild hyperhomocysteinemia and cardiovascular disease or all-cause mortality. Starting at a plasma homocysteine concentration of approximately 10 micromol/l, the risk increase follows a linear dose-response relationship with no specific threshold level. Hyperhomocysteinemia as an independent risk factor for cardiovascular disease is thought to be responsible for about 10 percent of total risk. Elevated plasma homocysteine levels (> 12 micromol/l; moderate hyperhomocysteinemia) are considered cytotoxic and are found in 5 to 10 percent of the general population and in up to 40 percent of patients with vascular disease. Additional risk factors (smoking, arterial hypertension, diabetes, and hyperlipidemia) may additively or, by interacting with homocysteine, synergistically (and hence overproportionally) increase overall risk. Hyperhomocysteinemia is associated with alterations in vascular morphology, loss of endothelial antithrombotic function, and induction of a procoagulant environment. Most known forms of damage or injury are due to homocysteine-mediated oxidative stresses. Especially when acting as direct or indirect antagonists of cofactors and enzyme activities, numerous agents, drugs, diseases, and life style factors have an impact on homocysteine metabolism. Folic acid deficiency is considered the most common cause of hyperhomocysteinemia. An adequate intake of at least 400 microg of folate per day is difficult to maintain even with a balanced diet, and high-risk groups often find it impossible to meet these folate requirements. Based on the available evidence, there is an increasing call for the diagnosis and treatment of elevated homocysteine levels in high-risk individuals in general and patients with manifest vascular disease in particular. Subjects of both populations should first have a baseline homocysteine assay. Except where manifestations are already present, intervention, if any, should be guided by the severity of hyperhomocysteinemia. Consistent with other working parties and consensus groups, we recommend a target plasma homocysteine level of < 10 micromol/l. Based on various calculation models, reduction of elevated plasma homocysteine concentrations may theoretically prevent up to 25 percent of cardiovascular events. Supplementation is inexpensive, potentially effective, and devoid of adverse effects and, therefore, has an exceptionally favorable benefit/risk ratio. The results of ongoing randomized controlled intervention trials must be available before screening for and treatment of hyperhomocysteinemia can be recommended for the apparently healthy general population.     

Effect of chronic alcohol consumption on total plasma homocysteine level in rats

BACKGROUND: Chronic alcoholism in humans is associated with the development of hyperhomocysteinemia, the mechanism of which remains unclear. Among the causes of hyperhomocysteinemia is depletion of folate, vitamin B12, or vitamin B6. Population-based studies indicate that folate is the strongest vitamin determinant of hyperhomocysteinemia and, in most settings, folate supplementation effectively lowers elevated homocysteine levels. However, it is not clear whether folate deficiency is the cause of alcohol-related hyperhomocysteinemia. METHODS: In the present study, 10 male Sprague Dawley rats were fed ethanol-containing Lieber-DeCarli diets with 13 mg of folic acid per kilogram of diet. This represents a folate intake more than 20 times the basal requirement. Ethanol represented 36% of total energy, which yielded a concentration of 6.2% (vol/vol). The same number of rats were pair-fed with isocaloric control diets that contained an identical level of folate in which ethanol was entirely replaced by maltodextrin. RESULTS: At the end of 4 weeks, alcohol-fed rats did not show any significant reduction in plasma or hepatic folate concentrations, plasma pyridoxal-5'-phosphate concentration, or plasma vitamin B12 concentration. On the other hand, alcohol-fed rats were significantly hyperhomocysteinemic (17.24 +/- 4.63 micromol/liter,p < 0.01) compared to the nonalcohol group (10.73 +/- 2.76 micromol/liter). Alcohol-fed rats also had a significantly lower hepatic S-adenosylmethionine and higher hepatic S-adenosylhomocysteine levels. CONCLUSIONS: Chronic alcohol consumption produces hyperhomocysteinemia by a mechanism that is related to interference with one-carbon metabolism, and not through vitamin depletion.     

Homocysteine: overview of biochemistry, molecular biology, and role in disease processes

Homocysteine is derived from the essential amino acid methionine and plays a vital role in cellular homeostasis in man. Homocysteine levels depend on its synthesis, involving methionine adenosyltransferase, S-adenosylmethionine-dependent methyltransferases such as glycine N-methyltransferase, and S-adenosylhomocysteine hydrolase; its remethylation to methionine by methionine synthase, which requires methionine synthase reductase, vitamin B (12), and 5-methyltetrahydrofolate produced by methylenetetrahydrofolate reductase or betaine methyltransferase; and its degradation by transsulfuration involving cystathionine beta-synthase. The control of homocysteine metabolism involves changes of tissue content or inherent kinetic properties of the enzymes. In particular, S-adenosylmethionine acts as a switch between remethylation and transsulfuration through its allosteric inhibition of methylenetetrahydrofolate reductase and activation of cystathionine beta-synthase. Mutant alleles of genes for these enzymes can lead to severe loss of function and varying severity of disease. Several defects lead to severe hyperhomocysteinemia, the most common form being cystathionine beta-synthase deficiency, with more than a hundred reported mutations. Less severe elevations of plasma homocysteine are caused by folate and vitamin B (12) deficiency, and renal disease and moderate hyperhomocysteinemia are associated with several common disease states such as cardiovascular disease. Homocysteine toxicity is likely direct or caused by disturbed levels of associated metabolites; for example, methylation reactions through elevated S-adenosylhomocysteine.     

Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice

Deficiency of methylenetetrahydrofolate reductase (MTHFR) predisposes to hyperhomocysteinemia and vascular disease. We tested the hypothesis that heterozygous disruption of the Mthfr gene sensitizes mice to diet-induced hyperhomocysteinemia and endothelial dysfunction. Mthfr(+/-) and Mthfr(+/+) mice were fed 1 of 4 diets: control, high methionine (HM), low folate (LF), or high methionine/low folate (HM/LF). Plasma total homocysteine (tHcy) was higher with the LF and HM/LF diets than the control (P<.01) or HM (P<.05) diets, and Mthfr(+/-) mice had higher tHcy than Mthfr(+/+) mice (P<.05). With the control diet, the S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratio was lower in the liver and brain of Mthfr(+/-) mice than Mthfr(+/+) mice (P<.05). SAM/SAH ratios decreased further in Mthfr(+/+) or Mthfr(+/-) mice fed LF or LF/HM diets (P<.05). In cerebral arterioles, endothelium-dependent dilation to 1 or 10 microM acetylcholine was markedly and selectively impaired with the HM/LF diet compared with the control diet for both Mthfr(+/+) (maximum dilation 5% +/- 2% versus 21% +/- 4%; P<.01) and Mthfr(+/-) (6% +/- 2% versus 21% +/- 3%; P<.01) mice. These findings demonstrate that the Mthfr(+/-) genotype sensitizes mice to diet-induced hyperhomocysteinemia and that hyperhomocysteinemia alters tissue methylation capacity and impairs endothelial function in cerebral microvessels.     

Homocysteine levels in vegetarians versus omnivores

Vitamin B(12), folate, and vitamin B(6) are the main determinants of homocysteinemia. The vegan diet provides no vitamin B(12), but also less strict forms of alternative nutrition may suffer from a deficit of this vitamin. The plasma homocysteine level was measured in alternative nutrition groups of adults (lacto- and lactoovovegetarians, n = 62; vegans, n = 32) and compared with the levels in a group consuming traditional diet (n = 59), omnivores). In the group of vegetarians the average homocysteine level is 13.18 vs. 10.19 micromol/l in omnivores; the frequency of hyperhomocysteinemia is 29 vs. 5% in omnivores. In the group of vegans the average homocysteine value is 15.79 micromol/l (53% of the individual values exceeded 15 micromol/l). Omnivores consume the recommended amount of methionine; however, in individuals consuming an alternative diet, the intake of methionine is deficient (assessed by food frequency questionnaire; lower content of methionine in plant proteins). Under conditions of lower methionine availability the remethylation pathway prevails; therefore, vitamin B(12) and folate were evaluated in relation to the homocysteine level. The serum vitamin B(12) levels are significantly lower in the alternative nutrition groups (214.8 pmol/l in vegetarians, 140.1 pmol/l in vegans vs. 344.7 pmol/l in omnivores); a deficit (<179.0 pmol/l) was found in 26% of the vegetarians and in 78% of the vegans vs. 0% in omnivores. The serum folate levels were within the range of reference values in all groups; however, they were significantly lower in omnivores. The results show that the mild hyperhomocysteinemia in alternative nutrition is a consequence of vitamin B(12) deficiency.     

Analytic Approaches for the Treatment of Hyperhomocysteinemia and Its Impact on Vascular Disease

Homocysteine is an intermediary metabolite in the methionine cycle. Accumulation of homocysteine is caused either by mutation of relevant genes or by nutritional depletion of related vitamin(s). This review covers the historical background of hyperhomocysteinemia in which indispensable subjects in relation to underlying pathophysiological processes are discussed with the view of metabolism and genetics of folate and methionine cycles. This review emphasizes the unique role of homocysteine that is clearly distinct from other risk factors, particularly cholesterol in the development of vascular disease. The critical issue in understanding the role of homocysteine is the relation with plasma folic acid. The majority of subjects with homocysteine >?15 μmol/L exhibit plasma folate <?9 nmol/ L, indicating that depletion of folate is the main cause of hyperhomocysteinemia irrespective of the presence or absence of vascular disease. Furthermore, only the group of subjects with homocysteine levels >?15 μmol/L demonstrated a higher prevalence of vascular disease. Analytic approaches to treat hyperhomocysteinemia are discussed in which stepwise administration with nutritional doses of folic acid, 5-methyitetrahydrofolate (5-MTHF), and betaine is provided singly or by combined manner based on clinical and laboratory evaluations. Whether correction of hyperhomocysteinemia is able to prevent the development of homocysteine-associated vascular disease remains an unresolved issue. The review discussed a biochemical and mechanistic approach to resolve questions involved in the relation between homocysteine and the development of atherosclerotic vascular disease.     

Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-sectional study

OBJECTIVE: Homocysteine is a sulfur-containing amino acid formed during the demethylation of methionine. Vitamin B12 and folate deficiency and therapy with antifolate drugs may predispose patients with inflammatory bowel disease (IBD) to hyperhomocysteinemia. The known associations between hyperhomocysteinemia and smoking, osteoporosis, and thrombosis make it an interesting candidate as a pathogenetic link in IBD. The aim of this study was to identify the prevalence and risk factors of hyperhomocysteinemia in patients with IBD. METHODS: Sixty-five consecutive IBD patients were recruited from a tertiary outpatient gastroenterology practice. Fasting plasma homocysteine levels were measured, along with vitamin B12 and folate. Data regarding medication use, multivitamin use, disease location and severity, and extraintestinal manifestations of IBD were gathered. Homocysteine levels in 138 healthy control subjects were compared with the IBD cohort, and adjustments for age and sex were made using logistic regression. Multivariate analysis was performed to seek predictors of homocysteine levels. RESULTS: The mean age in the IBD cohort was 42+/-13.4 yr (+/-SD), and 43% were male. The mean disease duration was 13.8+/-9.4 yr, and 32% had used steroids within the last 3 months. Immunomodulator therapy had been used in 32%, and 75% had had an intestinal resection. Osteoporosis was present in 33% of patients. Five patients had experienced venous thrombosis or stroke, but only one of these had hyperhomocysteinemia. Of the 10 IBD patients (15.4%) with hyperhomocysteinemia, only two had vitamin B12 deficiency. The homocysteine levels in the IBD cohort cases and controls were 8.7 and 6.6 micromol/L, respectively (p < 0.05). IBD significantly increased the risk of hyperhomocysteinemia (adjusted odds ratio = 5.9 [95% CI: 1.5-24]). Advanced age, male sex, vitamin B12 deficiency or lower vitamin B12 serum levels, and multivitamin therapy were independently associated with higher homocysteine levels in the multivariate analysis (R2 = 0.55; p = 0.001). CONCLUSIONS: Hyperhomocysteinemia is significantly more common in patients with IBD compared with healthy controls, and is associated with lower (but not necessarily deficient) vitamin B12 levels.     

Plasma homocysteine after insulin infusion in type II diabetic patients with and without methionine intolerance.

BACKGROUND: A high prevalence of hyperhomocysteinemia has been reported in type II diabetic patients with documented vascular disease; hence the hypothesis that hyperhomocysteinemia may contribute to overall mortality in diabetic patients. The link between insulin and homocysteine metabolism has not been completely clarified yet; in particular, only few data are available on the effects of insulin in vivo on homocysteine metabolism in the presence of abnormalities of sulphur amino acid metabolism (methionine intolerance). MATERIALS AND METHODS: To establish whether methionine intolerance and which of its determinants could influence total plasma homocysteine in response to insulin infusion in vivo in type II diabetic patients, we submitted 18 patients (Group A) with normal and 18 patients with abnormal (hyperhomocysteinemia) (Group B) response to oral methionine load to a glucose/clamp study. At time 0, and 30, 60 and 120 minutes after hyperinsulinemia, homocysteine and methionine plasma levels were assessed. In order to evaluate the cause of methionine intolerance, all patients were assayed for fasting homocysteine-cysteine ratio (as a marker of suspected heterozygosis for cystathionine-beta-synthase deficit), MTHFR C (677)T status and homocysteine-related vitamin status (serum vitamin B (6) [PLP], vitamin B (12) and folate). RESULTS: After hyperinsulinemia, plasma methionine was reduced (by about - 30 % at 120 minutes vs. basal values) within both groups, whereas tHcy tend to decrease in group A following insulin administration (up to - 6.6 +/- 3.6 % vs. basal values at 120 minutes) with a significantly higher variability, while in patients with "methionine intolerance" (group B) tHcy tended to increase (up to + 29.05 +/- 8.3 % vs. basal values at 120 min from the clamp). Serum folic acid (7.45 +/- 2.8 vs. 4.82 +/- 2.5 nmol/L, p < 0.05), Vit. B (12) (348 +/- 78 vs. 242 +/- 65 pmol/L, p < 0.05) and PLP (84.1 +/- 23.6 vs. 50.6 +/- 32.4 nmol/L; p < 0.01) were significantly higher in group A than in group B; PLP levels significantly correlated with homocysteine after 4 h methionine load (n = 36; r = - 0.327, p < 0.05); group A showed also a significantly lower prevalence of suspected heterozygosis for cystathionine-beta-synthase deficit (1/18 [11.1 %] vs. 5/18 [33.3 %], p < 0.05) and MTHFR T allele presence (4/18 [22.2 %] vs. 11/18 [61.1 %], p < 0.01). A stepwise regression analysis with tHcy plasma level variations (event A = reduction; event B = increase) as the dependent variable showed that low serum folate and PLP levels and presence of MTHFR T allele were the variables associated with insulin-induced tHcy increase. CONCLUSIONS: Methionine intolerance may influence the effect of insulin administration on plasma homocysteine in patients affected by type 2 diabetes. To prevent a possible acute (and repeated) hyperhomocysteinemia due to insulin administration in cases of methionine intolerance, it may be useful to assess the presence of methionine intolerance (tHcy after oral methionine loading) and Hcy-related vitamin status in all patients due to be subjected to insulin therapy.     

高同型半胱氨酸血症大鼠冠状动脉内皮细胞单核细胞趋化蛋白1的表达

目的观察高同型半胱氨酸血症对大鼠冠状动脉内皮细胞表达单核细胞趋化蛋白1的影响,以明了冠状动脉粥样硬化性心脏病的发病机制。方法24只大鼠随机分成正常饮食对照组、高蛋氨酸饮食组、高蛋氨酸 叶酸饮食组、高半胱氨酸饮食组。每组6只,分别给予普通饲料;普通饲料加1.7%蛋氨酸;普通饲料加1.7%蛋氨酸和0.006%叶酸;普通饲料加1.2%半胱氨酸。饲养6周,采用高效液相色谱荧光检测法测定血浆总同型半胱氨酸浓度,免疫组织化学染色法检测大鼠冠状动脉左主干和左前降支内皮细胞单核细胞趋化蛋白1的表达。结果喂以高蛋氨酸饲料6周,可诱导大鼠高同型半胱氨酸血症。与正常饮食对照组比较,高蛋氨酸饮食组大鼠血浆总同型半胱氨酸浓度显著升高(P<0.01),冠状动脉内皮单核细胞趋化蛋白1的表达水平明显增强;高蛋氨酸 叶酸饮食组大鼠血浆总同型半胱氨酸水平较高蛋氨酸饮食组显著降低(P<0.01),其冠状动脉内皮单核细胞趋化蛋白1的表达水平也降低;高半胱氨酸饮食组大鼠血浆总同型半胱氨酸浓度,以及冠状动脉内皮单核细胞趋化蛋白1的表达水平与正常饮食对照组比较差异无显著性。结论高同型半胱氨酸血症促进了大鼠冠状动脉内皮细胞表达单核细胞趋化蛋白1,在冠状动脉粥样硬化性心脏病的发生和发展中起着重要的作用。     

Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis]

Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6). Today, hyperhomocysteinemia should be considered an important risk factor for atherosclerotic vascular and venous thromboembolic diseases. Homocysteine-plasma levels above the 95th percentile were found to be associated with a 2 to 3-fold elevated relative risk for deep-vein thrombosis and pulmonary embolism. Moreover, mild hyperhomocysteinemia has been shown to be associated with a 2 to 4-fold increased relative risk for coronary artery disease, cerebrovascular disease, and peripheral arterial occlusive disease. Several mechanisms have been proposed by which hyperhomocysteinemia contributes to atherogenesis and thrombogenesis. Several studies have shown that hyperhomocysteinemia can be corrected by supplementation of folic acid, cobalamin and vitamin B6. Clinical trials are urgently needed which investigate the preventive effect of supplementation of these vitamins on thrombotic diseases.     

Homocysteine: a novel risk factor in vascular disease

Homocysteine is a sulphydryl-containing aminoacid derived from the metabolic demethylation of methionine. Moderately raised concentrations of total homocysteine (tHcy) have been correlated with an increased risk of atherothrombotic vascular events. The prevalence of hyperhomocysteinaemia has been estimated to be about 5% in the general population, and 13–47% among patients with symptomatic atherosclerotic vascular disease. Nutritional deficiencies in the vitamin cofactors (folate, vitamin B12, and vitamin B6) required for homocysteine metabolism may promote hyperhomocysteinaemia. Clinical and experimental studies suggest that high homocysteine concentrations may cause the atherogenic and thrombotic tendencies of homocystinuric and hyperhomocysteinaemic patients. Experimental evidence suggests that the atherogenic propensity associated with hyperhomocysteinaemia results from endothelial dysfunction and injury followed by platelet activation and thrombus formation. The treatment of hyperhomocysteinaemia varies with the underlying cause; however, vitamin supplementation (with folic acid, pyridoxine [vitamin B₆], and vitamin B₁₂) is generally effective in reducing homocysteine concentrations. Before advocating widespread screening of patients with atherosclerotic vascular disease, we must have a clearer understanding of the clinical efficacy of potential therapeutic interventions. Prospective, randomized clinical trials, however, will be necessary to determine the effect of vitamin supplementation on cardiovascular morbidity and mortality.     

Homocysteine: A new cardiac risk factor?

Elevated plasma homocysteine levels have recently been implicated as a new risk factor for coronary artery disease. In this article, homocysteine metabolism, secondary causes of elevated plasma homocysteine, and the potential mechanism of vascular damage in hyperhomocysteinemia are briefly reviewed. The current clinical evidence implicating hyperhomocysteinemia as a risk factor for coronary artery disease, as well as the data regarding the effects of B vitamin supplementation on homocysteine concentrations, are also reviewed. The current recommendation of the authors is to treat patients with known coronary artery disease or those who are considered to be at high risk for coronary artery disease with 400 microg of folate supplementation. Until prospective clinical trial data become available, this approach appears to be a safe and effective way to approach this patient population.     

Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Effects of pyridoxine and folic acid treatment

Severe homocysteinemia due to genetic defects either of pyridoxal 5-phosphate (PLP)-dependent cystathionine beta-synthase (CBS) or of enzymes in vitamin B12 and folate metabolism is associated with very early-onset vascular disease. Therefore, we studied homocysteine metabolism in 72 patients presenting before the age of 55 years with occlusive arterial disease of cerebral, carotid, or aorto-iliac vessels. Twenty patients (28%) had basal homocysteinemia; and 26 patients (36%) had abnormal increases of plasma homocysteine after peroral methionine loading, which exceeded the highest value for 46 comparable controls and was within the range for 20 obligate heterozygotes for homocystinuria due to CBS deficiency. Basal plasma homocysteine content was strongly and negatively correlated to vitamin B12 and folate concentrations. Plasma PLP was depressed in most patients but there was no correlation between PLP and homocysteine values. In 20 patients, treatment with pyridoxine hydrochloride (240 mg/day) and folic acid (10 mg/day) reduced fasting homocysteine after 4 weeks by a mean of 53%, and methionine response by a mean of 39%. These data show that a substantial proportion of patients with early-onset vascular disease have impaired homocysteine metabolism, which may contribute to vascular disease, and that the impaired metabolism can be improved easily and without side effects.     

Occurrence of hyperhomocysteinemia 1 year after gastroplasty for severe obesity

Severe obesity exposes one to an increased risk of cardiovascular mortality. Gastroplasty has been shown to induce substantial weight loss and to improve the atherogenic profile of severely obese subjects. However, vitamin deficiencies after gastroplasty have been reported. Because hyperhomocysteinemia, an independent risk factor for cardiovascular disease, is influenced by nutritional status (and especially by folate intake), we hypothesized that a marginal folate deficiency induced by gastroplasty could promote hyperhomocysteinemia. Thus, plasma homocysteine concentrations were measured by high-performance liquid chromatography in 53 severely obese patients (body mass index = 42 +/- 1), before and 1 yr after vertical gastroplasty. Plasma homocysteine concentrations increased, on an average, from 9.9 +/- 0.4 to 12.8 +/- 0.6 micromol/L (P < 0.0001). This increase in homocysteine levels was observed in two thirds of the subjects, leading to clear-cut hyperhomocysteinemia (>15 micromol/L) in 32%. The changes in homocysteine concentrations were correlated to weight loss (P < 0.001) and to decrease in plasma folate concentrations (P < 0.01). Whereas gastroplasty induced a mean 32-kg weight loss and a striking improvement in conventional risk factors, the occurrence of iatrogenic hyperhomocysteinemia might hamper the benefit of surgery on cardiovascular risk in most of the patients. Our results further support use of a systematic efficient folate supplementation after gastroplasty.     

B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice

In older adults, mildly elevated plasma total homocysteine (hyperhomocysteinemia) is associated with increased risk of cognitive impairment, cerebrovascular disease, and Alzheimer's disease, but it is uncertain whether this is due to underlying metabolic, neurotoxic, or vascular processes. We report here that feeding male C57BL6/J mice a B-vitamin-deficient diet for 10 weeks induced hyperhomocysteinemia, significantly impaired spatial learning and memory, and caused a significant rarefaction of hippocampal microvasculature without concomitant gliosis and neurodegeneration. Total hippocampal capillary length was inversely correlated with Morris water maze escape latencies (r = −0.757, P < 0.001), and with plasma total homocysteine (r = −0.631, P = 0.007). Feeding mice a methionine-rich diet produced similar but less pronounced effects. Our findings suggest that cerebral microvascular rarefaction can cause cognitive dysfunction in the absence of or preceding neurodegeneration. Similar microvascular changes may mediate the association of hyperhomocysteinemia with human age-related cognitive decline.