s-adenosylhomocysteine and Cardiovascular-Diseases

Homocysteine (Hcy) is methylated by methionine synthase to form methionine with methyl-cobalamin as a cofactor. The reaction demethylates 5-methyltetrahydrofolate to tetrahydrofolate, which is required for DNA and RNA synthesis. Deficiency of either of the cobalamin (Cbl) and/or folate cofactors results in elevated Hcy and megaloblastic anemia. Elevated Hcy is a sensitive biomarker of Cbl and/or folate status and more specific than serum vitamin assays. Elevated Hcy normalizes when the correct vitamin is given. Elevated Hcy is associated with alcohol use disorder and drugs that target folate or Cbl metabolism, and is a risk factor for thrombotic vascular disease. Elevated methionine and cystathionine are associated with liver disease. Elevated Hcy, cystathionine, and cysteine, but not methionine, are common in patients with chronic renal failure. Higher cysteine predicts obesity and future weight gain. Serum S-adenosylhomocysteine (AdoHcy) is elevated in Cbl deficiency and chronic renal failure. Drugs that require methylation for catabolism may deplete liver S-adenosylmethionine and raise AdoHcy and Hcy. Deficiency of Cbl or folate or perturbations of their metabolism cause major changes in sulfur amino acids.

Topics: Alcoholism; Amino Acids, Sulfur; Anemia, Megaloblastic; Biomarkers; Cardiovascular Diseases; Folic Acid; Folic Acid Deficiency; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Liver Diseases; Nutritional Status; Obesity; S-Adenosylhomocysteine; Vitamin B 12; Vitamin B 12 Deficiency

Homocysteine (Hcy) is a sulfur-containing non-proteinogenic amino acid formed during the metabolism of the essential amino acid methionine. Hcy is considered a risk factor for atherosclerosis and cardiovascular disease (CVD), but the molecular basis of these associations remains elusive. The impairment of endothelial function, a key initial event in the setting of atherosclerosis and CVD, is recurrently observed in hyperhomocysteinemia (HHcy). Various observations may explain the vascular toxicity associated with HHcy. For instance, Hcy interferes with the production of nitric oxide (NO), a gaseous master regulator of endothelial homeostasis. Moreover, Hcy deregulates the signaling pathways associated with another essential endothelial gasotransmitter: hydrogen sulfide. Hcy also mediates the loss of critical endothelial antioxidant systems and increases the intracellular concentration of reactive oxygen species (ROS) yielding oxidative stress. ROS disturb lipoprotein metabolism, contributing to the growth of atherosclerotic vascular lesions. Moreover, excess Hcy maybe be indirectly incorporated into proteins, a process referred to as protein N-homocysteinylation, inducing vascular damage. Lastly, cellular hypomethylation caused by build-up of

Topics: Atherosclerosis; Cardiovascular Diseases; Endothelial Cells; Homocysteine; Humans; Hydrogen Sulfide; Hyperhomocysteinemia; Methionine; Nitric Oxide; Reactive Oxygen Species; S-Adenosylhomocysteine

Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.

Topics: Biomarkers; Cardiovascular Diseases; Cystathionine; Dietary Supplements; Folic Acid; Free Radicals; Homocysteine; Humans; Hyperhomocysteinemia; Iron; Lipoproteins, LDL; Methionine; Risk Factors; S-Adenosylhomocysteine; Vitamin B Complex

Nutritional epigenetics has emerged as a novel mechanism underlying gene-diet interactions, further elucidating the modulatory role of nutrition in aging and age-related disease development. Epigenetics is defined as a heritable modification to the DNA that regulates chromosome architecture and modulates gene expression without changes in the underlying bp sequence, ultimately determining phenotype from genotype. DNA methylation and post-translational histone modifications are classical levels of epigenetic regulation. Epigenetic phenomena are critical from embryonic development through the aging process, with aberrations in epigenetic patterns emerging as aetiological mechanisms in many age-related diseases such as cancer, CVD and neurodegenerative disorders. Nutrients can act as the source of epigenetic modifications and can regulate the placement of these modifications. Nutrients involved in one-carbon metabolism, namely folate, vitamin B12, vitamin B6, riboflavin, methionine, choline and betaine, are involved in DNA methylation by regulating levels of the universal methyl donor S-adenosylmethionine and methyltransferase inhibitor S-adenosylhomocysteine. Other nutrients and bioactive food components such as retinoic acid, resveratrol, curcumin, sulforaphane and tea polyphenols can modulate epigenetic patterns by altering the levels of S-adenosylmethionine and S-adenosylhomocysteine or directing the enzymes that catalyse DNA methylation and histone modifications. Aging and age-related diseases are associated with profound changes in epigenetic patterns, though it is not yet known whether these changes are programmatic or stochastic in nature. Future work in this field seeks to characterise the epigenetic pattern of healthy aging to ultimately identify nutritional measures to achieve this pattern.

Topics: Aging; Animals; Cardiovascular Diseases; Diet; DNA Methylation; Epigenesis, Genetic; Epigenomics; Humans; Micronutrients; Neoplasms; Neurodegenerative Diseases; S-Adenosylhomocysteine; S-Adenosylmethionine

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Most previous investigations focused on the role of homocysteine as direct pathogenetic factor for these adverse vascular events. However, the exact pathophysiological mechanism is still unknown. In this review we discuss the hypothesis that a decreased extracellular concentration of adenosine could contribute to the adverse cardiovascular effects of hyperhomocysteinemia. Fundamental to this hypothesis is that, in vivo, any increase in the plasma concentration of homocysteine reflects an increased intracellular homocysteine concentration, which inevitably will result in a decrease in the adenosine concentration. In this situation, the hydrolase reaction catalysed by S-adenosylhomocysteine hydrolase will reverse and S-adenosylhomocysteine will accumulate at the expense of adenosine. Stimulation of adenosine receptors by adenosine results in various cardio- and vasoprotective actions, like modulation of vascular resistance, presynaptic inhibition of norepinephrine release, ischaemic preconditioning, inhibition of platelet aggregation, modulation of inflammation and regulation of vascular cell proliferation and death. In this respect, a decrease in the adenosine concentration could contribute significantly to the cardiovascular effects of hyperhomocysteinemia.

Topics: Adenosine; Cardiovascular Diseases; Homeostasis; Homocysteine; Humans; Hyperhomocysteinemia; Receptors, Purinergic P1; S-Adenosylhomocysteine

Studies have shown that hyperhomocysteinemia is an important and independent risk factor for a variety of human cardiovascular diseases. In this paper, a unifying hypothesis is proposed which suggests that hyperhomocysteinemia may exert its pathogenic effects largely through metabolic accumulation of S-adenosyl-L-homocysteine, a strong noncompetitive inhibitor of the catechol-O-methyltransferase (COMT)-mediated methylation metabolism of various catechol substrates (such as catecholamines and catechol estrogens). In the case of endogenous catecholamines in peripheral tissues, inhibition of their methylation by S-adenosyl-L-homocysteine will result in elevation of blood or tissue levels of catecholamines, and consequently, over-stimulation of the cardiovascular system's functions. Moreover, because the vasculature is constantly exposed to high levels of endogenous catecholamines (due to high levels of circulating neurohormone epinephrine plus rich innervation with sympathetic nerve terminals), vascular endothelial cells would incur chronic cumulative damage caused by the large amounts of the oxidative products (catechol quinones/semiquinones and oxyradicals) generated from endogenous catecholamines. This mechanistic explanation for the vascular toxicity of hyperhomocysteinemia is supported by many experimental findings, and it also fully agrees with the known protective effects of folate, vitamins B6 and B12 in hyperhomocysteinemic patients. In addition, based on the predictable effects of hyperhomocysteinemia on the methylation of catecholamines in the central nervous system as well as on the methylation of catechol estrogens in estrogen target organs, it is also suggested that hyperhomocysteinemia is an important risk factor for the development of neurodegerative disorders (Parkinson's and Alzheimer's diseases) and estrogen-induced hormonal cancers. More studies are warranted to test these intriguing ideas.

Topics: Animals; Cardiovascular Diseases; Catechol O-Methyltransferase Inhibitors; Catecholamines; Homocysteine; Humans; S-Adenosylhomocysteine

Over the last 30 years, a growing body of evidence has documented the role of hyperhomocysteinemia (HHcy) as an independent vascular risk factor. However, the mechanisms through which elevated circulating levels of homocysteine (Hcy) cause vascular injury and promote thrombosis remain elusive. Most findings have been achieved in in vitro studies employing exceedingly high concentrations of Hcy, whereas only a few studies have been carried out in vivo in humans. In homocystinuric patients, homozygotes for mutations of the gene coding for the cystathionine beta-synthase enzyme, abnormalities of coagulation variables reflecting a hypercoagulable state, have been reported. In vitro studies provide a biochemical background for such a state. In homocystinuric patients, an in vivo platelet activation has also been reported. The latter abnormality is not corrected by the bolus infusion of concentrations of hirudin, which determines a long-lasting impairment of the conversion of fibrinogen to fibrin by thrombin; in contrast, it appears at least in part lowered by the administration of the antioxidant drug probucol. During the autooxidation of Hcy in plasma, reactive oxygen species are generated. The latter initiate lipid peroxidation in cell membranes (potentially responsible for endothelial dysfunction) and in circulating lipoproteins. Oxidized low-density lipoproteins (LDL) may trigger platelet activation as well as some of the hemostatic abnormalities reported in such patients. Thus the oxidative stress induced by Hcy may be a key process in the pathogenesis of thrombosis in HHcy. Accumulation of adenosylhomocysteine in cells (a consequence of high circulating levels of homocysteine) inhibits methyltransferase enzymes, in turn preventing repair of aged or damaged cells. This mechanism has been recently documented in patients with renal failure and HHcy and provides an additional direction to be followed to understand the tendency to thrombosis in moderate HHcy.

Topics: Adolescent; Adult; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Cellular Senescence; Child; Endothelium, Vascular; Female; Genetic Predisposition to Disease; Homocysteine; Homocystinuria; Humans; Hyperhomocysteinemia; Lipid Peroxidation; Lipoproteins, LDL; Male; Methyltransferases; Oxidation-Reduction; Platelet Activation; Reactive Oxygen Species; Renal Insufficiency; Risk Factors; S-Adenosylhomocysteine; Thrombophilia; Thromboxane B2; Vitamin K

Vascular senescence, which is closely related to epigenetic regulation, is an early pathological condition in cardiovascular diseases including atherosclerosis. Inhibition of S-adenosylhomocysteine hydrolase (SAHH) and the consequent increase of S-adenosylhomocysteine (SAH), a potent inhibitor of DNA methyltransferase, has been associated with an elevated risk of cardiovascular diseases. This study aimed to investigate whether the inhibition of SAHH accelerates vascular senescence and the development of atherosclerosis.. The case-control study related to vascular aging showed that increased levels of plasma SAH were positively associated with the risk of vascular aging, with an odds ratio (OR) of 3.90 (95% CI, 1.17-13.02). Elevated pulse wave velocity, impaired endothelium-dependent relaxation response, and increased senescence-associated β-galactosidase staining were observed in the artery of SAHH. SAHH inhibition epigenetically upregulates Drp1 expression through repressing DNA methylation in endothelial cells, leading to vascular senescence and atherosclerosis. These results identify SAHH or SAH as a potential therapeutic target for vascular senescence and cardiovascular diseases.

Topics: Adenosylhomocysteinase; Animals; Atherosclerosis; Cardiovascular Diseases; Case-Control Studies; Endothelial Cells; Epigenesis, Genetic; Mice; Mitochondrial Dynamics; Pulse Wave Analysis; S-Adenosylhomocysteine

Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment.. We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans.. A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured.. Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant.. High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO concentrations but also to alterations in interrelated pathways such as lipids, phospholipids, and methylation. Elevated plasma TMAO concentrations likely reflect a specific metabolic pattern characterized by low HDL and phospholipids in addition to hypomethylation. This trial was registered at clinicaltrials.gov as NCT02586181 and NCT02588898.

Topics: Aged; Bacteria; Betaine; Cardiovascular Diseases; Choline; Creatinine; Diabetes Mellitus; Female; Gastrointestinal Microbiome; Humans; Lipoproteins, HDL; Male; Methylamines; Methylation; Middle Aged; Phosphatidylcholines; Phospholipids; S-Adenosylhomocysteine; S-Adenosylmethionine; Sex Factors

Although homocysteine has been proposed as a cardiovascular risk factor, interventional trials lowering homocysteine have not consistently demonstrated clinical benefit. Recent evidence proposed the homocysteine metabolite S-adenosylhomocysteine (SAH) rather than homocysteine itself as the real culprit in cardiovascular disease. Of note, SAH is predominantly excreted by the kidneys, and cannot be lowered by vitamin supplementation. Due to its cumbersome measurement, data from large studies on the association between SAH, kidney function and cardiovascular disease are not available.. We recruited 420 apparently healthy subjects into our I Like HOMe FU study. Among all study participants, we assessed parameters of C1 metabolism (homocysteine, SAH and S-adenosylmethionine), renal function (estimated glomerular filtration rate [eGFR]) and subclinical atherosclerosis (common carotid intima-media-thickness [IMT]). eGFR was estimated by the CKD-EPIcreat-cys equation.. Traditional cardiovascular risk factors and subclinical atherosclerosis were associated with SAH, but not with homocysteine (IMT vs SAH: r = 0.129; p = 0.010; IMT vs homocysteine: r = 0.009; p = 0.853). Moreover, renal function was more closely correlated with SAH than with homocysteine (eGFR vs SAH: r = -0.335; p < 0.001; eGFR vs homocysteine: r = -0.250; p < 0.001). The association between eGFR and SAH remained significant after adjustment for traditional cardiovascular risk factors.. In summary, cardiovascular risk factors, subclinical atherosclerosis and eGFR are more strongly associated with SAH than with homocysteine in apparently healthy subjects. Thus, SAH might represent a more promising target to prevent cardiovascular disease than homocysteine.

Topics: Asymptomatic Diseases; Atherosclerosis; Cardiovascular Diseases; Female; Glomerular Filtration Rate; Homocysteine; Humans; Male; Middle Aged; Risk Factors; S-Adenosylhomocysteine; S-Adenosylmethionine

S-adenosylmethionine (SAM), the unique methyl donor in DNA methylation, has been shown to lower lipopolysaccharide (LPS)-induced expression of the proinflammatory cytokine TNF-α and increase the expression of the anti-inflammatory cytokine IL-10 in macrophages. The aim of this study was to assess whether epigenetic mechanisms mediate the anti-inflammatory effects of SAM. Human monocytic THP1 cells were differentiated into macrophages and treated with 0, 500, or 1,000 μmol/l SAM for 24 h, followed by stimulation with LPS. TNFα and IL-10 expression levels were measured by real-time PCR, cellular concentrations of SAM and S-adenosylhomocysteine (SAH), a metabolite of SAM, were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and DNA methylation was measured with LC-MS/MS and microarrays. Relative to control (0 μmol/l SAM), treatment with 500 μmol/l SAM caused a significant decrease in TNF-α expression (-45%, P < 0.05) and increase in IL-10 expression (+77%, P < 0.05). Treatment with 1,000 μmol/l SAM yielded no significant additional benefits. Relative to control, 500 μmol/l SAM increased cellular SAM concentrations twofold without changes in SAH, and 1,000 μmol/l SAM increased cellular SAM sixfold and SAH fourfold. Global DNA methylation increased 7% with 500 μmol/l SAM compared with control. Following treatment with 500 μmol/l SAM, DNA methylation microarray analysis identified 765 differentially methylated regions associated with 918 genes. Pathway analysis of these genes identified a biological network associated with cardiovascular disease, including a subset of genes that were differentially hypomethylated and whose expression levels were altered by SAM. Our data indicate that SAM modulates the expression of inflammatory genes in association with changes in specific gene promoter DNA methylation.

Topics: Cardiovascular Diseases; Cell Line; DNA Methylation; Gene Expression Regulation; Gene Regulatory Networks; Humans; Inflammation; Interleukin-10; Macrophages; S-Adenosylhomocysteine; S-Adenosylmethionine; Tumor Necrosis Factor-alpha

Obesity, a feature of metabolic syndrome, is a risk factor for cardiovascular disease, and elevated plasma homocysteine is associated with increased cardiovascular risk. However, little published information is available concerning the effect of obesity on homocysteine metabolism.. Hepatic homocysteine metabolism was determined in male C57BL/6 mice fed a high-fat diet for 12 weeks.. High-fat diet increased plasma homocysteine but decreased hepatic homocysteine levels. Hepatic S-adenosylhomocysteine hydrolase levels were down-regulated in the obese mice, which was in part responsible for the decrease in hepatic S-adenosylmethionine/S-adenosylhomocysteine, which served as an index of transmethylation potential. Despite the decrease in hepatic cysteine, hepatic taurine synthesis was activated via up-regulation of cysteine dioxygenase. Hepatic levels of methionine adenosyltransferase I/III, methionine synthase, methylene tetrahydrofolate reductase, and gamma-glutamylcysteine ligase catalytic subunit were unchanged. Obese mice showed elevated betaine-homocysteine methyltransferase and decreased cystathionine beta-synthase activities, although the quantities of these enzymes were unchanged.. This study suggests that plasma homocysteine level is increased in obesity-associated hepatic steatosis, possibly as a result of increased hepatic homocysteine efflux along with an altered sulfur amino acid metabolism.

Topics: 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; Adenosylhomocysteinase; Amino Acids, Sulfur; Animals; Cardiovascular Diseases; Cystathionine beta-Synthase; Cysteine Dioxygenase; Diet, High-Fat; Dipeptides; Down-Regulation; Homocysteine; Lipid Peroxidation; Liver; Male; Methionine Adenosyltransferase; Methylenetetrahydrofolate Reductase (NADPH2); Mice; Mice, Inbred C57BL; Risk Factors; S-Adenosylhomocysteine; S-Adenosylmethionine; Triglycerides; Up-Regulation

The putative role of sulfur amino acids such as homocysteine (tHcy) as cardiovascular risk factors is controversial in chronic kidney disease (CKD). Although, S-adenosylhomocysteine (SAH) levels have been linked to CVD in non-renal populations, such relationship has not been evaluated in CKD.. Serum concentrations of S-adenosylmethionine (SAM), SAH and total homocysteine (tHcy) were determined by HPLC in 124 CKD stage 5 patients (GFR range 1-11 m/min) and 47 control subjects, and related to renal function, presence of CVD, inflammation and protein-energy wasting (PEW).. The levels of SAM and SAH were higher in CKD patients than in controls. Both SAM (rho=-0.19; P<0.05) and SAH (rho=-0.37, P<0.001) were inversely related to GFR. The concentrations of SAH were significantly higher (P<0.001) in patients with CVD than in non-CVD patients, (683 (201-3057) vs 485 (259-2620) nmol/L; median (range)) as opposed to tHcy levels, which were lower in CVD patients. While SAH was not associated with the presence of inflammation or PEW, it was a significant contributor (OR; 4.9 (CI 1.8-12.8), P<0.001) to CVD in a multinomial logistic regression model (pseudo r(2)=0.31).. Concentrations of serum SAH and SAM in CKD stage 5 patients are associated with renal function, but not with inflammation or PEW. Among the investigated sulfur amino acids, only SAH was independently associated with the presence of clinical signs of CVD. These findings suggest that while tHcy might be influenced by a number of confounding uremic factors, SAH levels may better reflect the putative increased cardiovascular risk of sulfur amino acid alterations in CKD patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Chromatography, High Pressure Liquid; Chronic Disease; Female; Homocysteine; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Predictive Value of Tests; S-Adenosylhomocysteine; S-Adenosylmethionine; Sensitivity and Specificity; Severity of Illness Index

It is unclear whether homocysteine itself is causal in the pathogenesis of cardiovascular disease. Alternatively or additionally, the association between homocysteine and cardiovascular disease may be because of its metabolic precursor, S-adenosylhomocysteine, or of the ratio of S-adenosylmethionine to S-adenosylhomocysteine. Therefore, it is relevant to know how these moieties are interrelated, and whether, as is the case for homocysteine, they are influenced by blood levels of folate, cobalamin or vitamin B6.. We cross-sectionally studied a population-based cohort of 97 Caucasian subjects aged 60-85 years. Concentrations of homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, folate, cobalamin and vitamin B6 were measured in fasting blood samples.. In multiple regression analysis, homocysteine was associated with vitamin B12 (per 50 pmol L-1 increase of cobalamin, change in homocysteine, -0.70 mmol L-1; 95% CI, -1.30 to -0.10 mmol L-1) and folate (per 100 nmol L-1 increase in erythrocyte folate, change in homocysteine, -0.68 mmol L-1; 95% CI -1.28 to -0.08 mmol L-1). S-adenosylhomocysteine, S-adenosylmethionine and the ratio of S-adenosylmethionine to S-adenosylhomocysteine were not associated with serum folate, cobalamin or vitamin B6, nor with erythrocyte folate. Furthermore, plasma homocysteine showed a negative correlation with the ratio of S-adenosylmethionine to S-adenosylhomocysteine in plasma (r = -0.27; P < 0.01) but not in erythrocytes.. In contrast to homocysteine, the plasma concentrations of S-adenosylhomocysteine and the ratio of S-adenosylmethionine to S-adenosylhomocysteine were not associated with the folate, cobalamin and vitamin B6 concentrations in the present study. If these precursors in part explain why homocysteine is associated with cardiovascular disease, homocysteine-lowering treatment with B vitamins may be less effective than currently expected, at least in an elderly population.

Topics: Aged; Aged, 80 and over; Body Constitution; Cardiovascular Diseases; Cross-Sectional Studies; Erythrocytes; Female; Folic Acid; Humans; Male; Middle Aged; Regression Analysis; S-Adenosylhomocysteine; S-Adenosylmethionine; Vitamin B 12; Vitamin B 6

The pathogenic mechanism of homocysteine's effect on cardiovascular risk is poorly understood. Recent studies show that DNA hypomethylation induced by increases in S-adenosylhomocysteine (AdoHcy), an intermediate of Hcy metabolism and a potent inhibitor of methyltransferases, may be involved in homocysteine-related pathology.. We measured fasting plasma total Hcy (tHcy), AdoHcy, and S-adenosylmethionine (AdoMet) and methylation in leukocytes in 17 patients with vascular disease and in 15 healthy, age- and sex-matched controls.. Patient with vascular disease had significantly higher plasma tHcy and AdoHcy concentrations and significantly lower plasma AdoMet/AdoHcy ratios and genomic DNA methylation. AdoMet concentrations were not significantly different between the two groups. More than 50% of the patients fell into the highest quartiles of plasma tHcy, AdoHcy, and [(3)H]dCTP incorporation/ micro g of DNA (meaning the lowest quartile of DNA methylation status) and into the lowest quartile of the AdoMet/AdoHcy ratios of the control group. Plasma tHcy was significantly correlated with plasma AdoHcy and AdoMet/AdoHcy ratios (n = 32; P < 0.001). DNA methylation status was significantly correlated with plasma tHcy and AdoHcy (n = 32; P < 0.01) but not with plasma AdoMet/AdoHcy ratios.. Global DNA methylation may be altered in vascular disease, with a concomitant increase in plasma tHcy and AdoHcy.

Topics: Cardiovascular Diseases; DNA Methylation; Homocysteine; Humans; Male; Middle Aged; S-Adenosylhomocysteine

Although plasma total homocysteine has been identified as an independent risk factor for vascular disease in a multitude of studies, there is a considerable overlap in values between patients at risk and control subjects. The difference in values can be used to distinguish statistically between the 2 groups, provided each group is large enough; however, discriminating between individual patients at risk and control subjects is difficult.. We investigated whether the precursor of homocysteine, S-adenosylhomocysteine, is a more sensitive indicator of risk.. We measured plasma total homocysteine, S-adenosylhomocysteine, S-adenosylmethionine, creatinine, folate, and vitamin B-12 in 30 patients with proven cardiovascular disease and 29 age- and sex-matched control subjects.. The homocysteine values (+/-SD) were 12.8 +/- 4.9 (95% CI: 11.0, 14.7) micromol/L for patients and 11.0 +/- 3.2 (9.8, 12.2) micromol/L for control subjects. The S-adenosylhomocysteine values were 40.0 +/- 20.6 (32.3, 47.7) nmol/L for patients and 27.0 +/- 6.7 (24.5, 30.0) nmol/L for control subjects (P = 0.0021). The S-adenosylmethionine values were 121.8 +/- 42.9 (105.8, 137.8) nmol/L for patients and 103.9 +/- 21.8 (95.6, 112.2) nmol/L for control subjects (P = 0.0493). The creatinine values were 110 +/- 27 (97, 120) micromol/L for patients and 97 +/- 9 (80, 100) micromol/L for control subjects (P = 0.0025). Values for folate and vitamin B-12 did not differ significantly between groups.. Plasma S-adenosylhomocysteine appears to be a much more sensitive indicator of the difference between patients with cardiovascular disease and control subjects than is homocysteine. Both plasma total homocysteine and S-adenosylhomocysteine are significantly correlated with plasma creatinine in patients.

Topics: Adult; Aged; Cardiovascular Diseases; Case-Control Studies; Creatinine; Female; Folic Acid; Homocysteine; Humans; Male; Middle Aged; Risk Factors; S-Adenosylhomocysteine; S-Adenosylmethionine; Sensitivity and Specificity; Vitamin B 12