Elevated Hcy Research Articles

Elevated Homocysteine Concentrations Decrease the Antihypertensive Effect of Angiotensin-Converting Enzyme Inhibitors in Hypertensive Patients.

We aimed to examine whether baseline homocysteine (Hcy) concentrations affect antihypertensive responses to enalapril treatment among previously untreated hypertensive patients (n=10 783) in the CSPPT (China Stroke Primary Prevention Trial). After a 3-week run-in treatment with a daily dose of 10 mg enalapril, eligible hypertensive patients were randomly assigned to a double-blind daily treatment of a tablet of either enalapril (10 mg) and folic acid (0.8 mg) or enalapril (10 mg) alone for a median of 4.5 years. After the 3-week treatment period with enalapril alone, the systolic blood pressure-lowering effect was significantly reduced by 1.39 (95% confidence interval 0.40-2.37) and 3.25 (95% confidence interval 1.98-4.52) mm Hg, respectively, in those with baseline Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001) as compared with those with Hcy concentration of <10 μmol/L. Similar results were observed after a 15-week treatment period with enalapril alone. After a median 4.5-year enalapril-based antihypertensive treatment period, compared with those with Hcy concentration of <10 μmol/L, the systolic blood pressure-lowering effect was still significantly reduced by 0.77 (95% confidence interval 0.01-1.53) and 1.70 (95% confidence interval 0.72-2.68) mm Hg, respectively, in those with Hcy concentrations of 10 to 15 and ≥15 μmol/L (P for trend <0.001). In addition, participants with higher baseline Hcy concentrations had persistently higher systolic blood pressure levels across the entire study treatment period. Similarly, baseline Hcy concentrations were inversely associated with diastolic blood pressure reduction during the short-term enalapril alone treatment. However, the inverse association between baseline Hcy and diastolic blood pressure reduction was attenuated and became insignificant after the long-term enalapril-based treatment period. Elevated Hcy concentrations significantly decreased the antihypertensive effect of the short-term and long-term enalapril-based antihypertensive treatment in previously untreated hypertensive patients.

Homocysteine, Alcoholism, and Its Potential Epigenetic Mechanism.

Alcohol is the most socially accepted addictive drug. Alcohol consumption is associated with some health problems such as neurological, cognitive, behavioral deficits, cancer, heart, and liver disease. Mechanisms of alcohol-induced toxicity are presently not yet clear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with amino acid homocysteine (Hcy), which has been linked with brain neurotoxicity. Elevated Hcy impairs with various physiological mechanisms in the body, especially metabolic pathways. Hcy metabolism is predominantly controlled by epigenetic regulation such as DNA methylation, histone modifications, and acetylation. An alteration in these processes leads to epigenetic modification. Therefore, in this review, we summarize the role of Hcy metabolism abnormalities in alcohol-induced toxicity with epigenetic adaptation and their influences on cerebrovascular pathology.

Correlation Between Hyperhomocysteinemia and Outcomes of Patients With Acute Myocardial Infarction.

Overwhelming clinical and epidemiological studies have identified elevated plasma total homocysteine (Hcy) as new important risk factor for atherosclerotic vascular disease. But the relationship between outcome and hyperhomocysteinemia in patients with acute myocardial infarction (AMI) has been rarely reported. This study aimed to evaluate the association between hyperhomocysteinemia and short-term outcomes of patients with AMI. Eight hundred five patients were divided into high Hcy level group (group H: N = 457) and low Hcy level group (group L: N = 348) according to the plasma Hcy levels of 15 mmol/L. The comparisons were made between 2 groups in the following aspects: sex, hypertension, diabetes, hyperlipidemia, the time for symptom from onset to percutaneous coronary intervention, homoccyteine, creatine phosphokinase isoenzyme (creatine kinase myocardial band), and the incidence of 30-day adverse events. The incidences of heart failure, cardiac rupture, death, and the total adverse cardiovascular events were statistically significantly higher in group H than in group L. But the incidence of postoperative angina pectoris and reinfarction was similar between groups. The results of logistic regression showed that the incidence of 30-day adverse events was closely related to the age and the level of Hcy. An elevated plasma total Hcy level in patients with AMI experienced pemutaneous coronary intervention may be related to the short-term outcomes. An elevated high plasma Hcy level also seems to be an independent predictor of 30-day cardiovascular events in patients with AMI.

Interaction of homocysteine, glutathione and 8-hydroxy-2′-deoxyguanosine in metabolic syndrome progression

PurposeThe role of homocysteine (Hcy) and associated oxidative stress processes in the metabolic syndrome (MetS) continuum has not been explored extensively. Changes in Hcy and associated oxidative stress in relation to the number of metabolic syndrome factors present are explored in this study. MethodParticipants (n=266) attending a rural diabetes screening clinic had their medical history recorded as well as body mass index, Hcy, glucose, cholesterol, glutathione (GSH), and 8-hydroxy-2-deoxyguanosine (8-OHdG) measured. ResultA significant elevation in Hcy (9.5μmol/L ±2 vs. 10.6μmol/L ±3, p=0.03) and 8-OHdG (307pg/mL ±516 vs. 1130pg/mL ±1155, p=0.0001) was observed between the noMetS and MetS groups. Hcy increased with the addition of MetS factors paralleled by 8-OHdG and GSH. A dramatic increase was seen in 8-OHdG, nearly doubling between 2 MetS and 3 MetS factors present (p=0.0001). ConclusionHomocysteine may be a useful marker together with 8-OHdG in assessing the extent of metabolic syndrome in a rural population.

Multi-Vitamin B Supplementation ReversesHypoxia-Induced Tau Hyperphosphorylation and Improves Memory Function in Adult Mice.

Hypobaric hypoxia (HH) leads to reduced oxygen delivery to brain. It could trigger cognitive dysfunction and increase the risk of dementia including Alzheimer's disease (AD). The present study was undertaken in order to examine whether B vitamins (B6, B12, folate, and choline) could exert protective effects on hypoxia-induced memory deficit and AD related molecular events in mice. Adult male Kunming mice were assigned to five groups: normoxic control, hypoxic model (HH), hypoxia+vitamin B6/B12/folate (HB), hypoxia+choline (HC), hypoxia+vitamin B6/B12/folate+choline (HBC). Mice in the hypoxia, HB, HC, and HBC groups were exposed to hypobaric hypoxia for 8 h/day for 28 days in a decompression chamber mimicking 5500 meters of high altitude. Spatial and passive memories were assessed by radial arm and step-through passive test, respectively. Levels of tau and glycogen synthase kinase (GSK)-3β phosphorylation were detected by western blot. Homocysteine (Hcy) concentrations were determined using enzymatic cycling assay. Mice in the HH group exhibited significant spatial working and passive memory impairment, increased tau phosphorylation at Thr181, Ser262, Ser202/Thr205, and Ser396 in the cortex and hippocampus, and elevated Hcy levels compared with controls. Concomitantly, the levels of Ser9-phosphorylated GSK-3β were significantly decreased in brain after hypoxic treatment. Supplementations of vitamin B6/B12/folate+choline could significantly ameliorate the hypoxia-induced memory deficits, observably decreased Hcy concentrations in serum, and markedly attenuated tau hyperphosphorylation at multiple AD-related sites through upregulating inhibitory Ser9-phosphorylated GSK-3β. Our finding give further insight into combined neuroprotective effects of vitamin B6, B12, folate, and choline on brain against hypoxia.

The Study of Homocysteine and Its Relationship with Oxidative Stress Biomarkers in Alzheimer’s Disease

Background: Increasing evidence suggests that oxidative stress is associated with normal aging and several neurodegenerative diseases, including Alzheimer’s disease. Alzheimer’s disease is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. Lipid peroxidation plays an important role in the development of dementia and AD. Elevated plasma homocysteine has been associated with pathogenesis of AD. The aim of the present study was to determine relationship between Hcy level and AD and its relationship oxidative stress biomarkers. Thirty AD patients and thirty healthy controls participated in the study. Plasma total Hcy and serum Malondialdehyde, activity of RBC-SOD, RBC-GSH (reduced Glutathione), serum Total thiol proteins and plasma Total Antioxidant Capacity were measured both in patients and controls using spectrophotometric methods. Competitive chemiluminescent immunoassay was used to analyse the total level of homocysteine in plasma. The lipid peroxidation in serum was measured by the level of TBARS. RBC-Superoxide dismutase activity and GSH were assayed by the method of Das and Burtis-Ashwood respectively. Serum thiol proteins (-SH) was determined by Habeeb method. TAC in plasma was analyzed by FRAP assay. Results: The plasma levels of Hcy and serum MDA in AD group are significantly higher than that of normal controls. The activity of RBC-SOD in AD group is significantly lower than that of normal control group. The significant decrease in the levels of RBC-GSH, total thiol proteins and TAC was observed in AD patients compared to controls. Furthermore, there were significant positive correlations between the plasma Hcy and MDA levels (r = +0.42, p= 0.01) and significant negative correlations between the levels plasma Hcy and TAC (r = -0.40, p= 0.02) in AD group. Conclusion: Hcy participate in pathogenesis of AD and elevated Hcy can promote significant oxidant damage and enhance oxidative stress in AD. This may represent additional risk factor pathways which conspire to produce AD. Increased oxidative stress and decreased antioxidants indicated its association with AD progression.

Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion.

Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level.

Association of serum homocysteine levels with metabolic syndrome and its components in adults

Objective To explore the relationship of serum homocysteine (Hcy) level with metabolic syndrome (MS) and its components. Methods A cross-sectional study was conducted in 594 adults consecutively sampled from people visiting Fuwai Hospital for physical examination between September and December 2012, including 160 MS participants (MS group) and 434 without MS participancs (without MS group). Serum Hcy levels, serum biochemical parameters, and anthropometric measurements of all the participants were collected. Binary logistic regression was used to assess the association of serum Hcy levels with MS and its components. Results No significant difference in Hcy levels was observed comparing the MS group and the without MS group [(12.2±7.0)μmol/L vs. (12.6±8.4)μmol/L, P>0.05]. Between participants with and without hyperhomocysteinemia (≥15 μmol/L vs. 0.05). Among participants having 0 to 5 metabolic abnormalities, there were no significant differences in serum Hcy levels [(12.3±7.4)μmol/L; (12.4±6.7)μmol/L; (13.2±11.2)μmol/L; (12.5±7.8)μmol/L; (11.2±2.7)μmol/L; (12.4±4.3)μmol/L; all P>0.05]. In a binary logistic regression model adjusted for age, gender, body mass index, total cholesterol, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein, neither MS nor its components were independent predictors of serum Hcy levels (all P>0.05). Conclusions Elevated serum Hcy levels are not associated with MS or its components in people without evident cardiovascular diseases. MS and elevated serum Hcy levels may cause cardiovascular diseases via different mechanisms. Key words: Homocysteine; Metabolic syndrome; Metabolic abnormalities; Cardiovascular disease

Association of Hyperhomocysteinemia with Stroke Recurrence after Initial Stroke

Homocysteine (Hcy) is closely associated with stroke. Despite the fact that Hcy has consistently been shown to predict development of recurrent stroke, prior studies on the association of Hcy and stroke subtypes have been inconclusive. Data from the Ege Stroke Registry were examined and 5-year follow-up data were analyzed. Multivariate survival analyses were undertaken using Cox proportional hazards models to determine the prognostic value of Hcy in different ischemic stroke subtypes. Of the 9522 patients with stroke, 307 (27%) with hyperhomocysteinemia (hHcy) had recurrent stroke. Univariate Cox regression model showed that hHcy group was associated with recurrent stroke (crude hazard ratio [HR] 1.16; 95% CI 1.02-1.30). But there was no such association in multivariate regression models (adjusted HR 1.11; 95% CI .97-1.26). hHcy was not associated with any ischemic stroke subtypes at 5 years. Univariate Cox regression model showed that hHcy group was associated with overall cardiovascular events (crude HR 1.44; 95% CI 1.32-1.57). However, this association no longer existed in multivariate regression models (adjusted HR 1.01; 95% CI .93-1.12). Higher plasma Hcy group was significantly associated with higher mortality compared with normal plasma Hcy group (OR 1.83; 95% CI .45-2.32). Our results showed that elevated Hcy is not associated independently with stroke recurrence and overall cardiovascular events in patients with ischemic stroke. There was no association between the hHcy and stroke recurrence in the stroke subtypes within 5 years.

Homocysteine Concentration Correlates with Baseline Clinical Status and Predicts Outcomes in a Large, Early Parkinson's Disease Cohort (DATATOP)

OBJECTIVETo determine the prevalence of elevated homocysteine (Hcy) concentration and its association with cognitive and motor function measurements in early untreated Parkinson's disease (PD).BACKGROUNDPrevious studies have identified a relationship of elevated circulating Hcy levels with the development of cognitive impairment in aging but this relationship has not been established in early PD. We sought to determine the prevalence of elevated Hcy status in a cohort with early untreated PD and whether it was associated with greater initial and subsequent morbidity.DESIGN/METHODSWe measured Hcy using 677 baseline samples from the DATATOP cohort of patients with early, untreated PD. Elevated Hcy status was defined as mildly elevated (&gt;11 μM) and moderately elevated (&gt;15 μM). Outcomes included motor assessments by Unified Parkinson's Disease Rating Scale (UPDRS scores) and cognitive assessments (Mini‐Mental Status test (MMSE) and Symbol Digits Modalities Test (SDMT)) at baseline and follow‐up, calculated as an annualized rate of change for those who participated for 6 months to 2 years. Baseline analyses were adjusted for sex, age, baseline B12 levels and treatment assignment. Change analyses were also adjusted for baseline value of the outcome.RESULTSThe geometric mean Hcy level was 9.5 μM and was mildly elevated in 26% (179/677) and moderately elevated in 7% (46/677) of subjects. Analysis of baseline features showed lower MMSE and SDMT scores in those with moderately elevated Hcy. Analysis of outcomes showed greater decline in MMSE scores in those with moderately elevated Hcy. No associations were observed between mildly elevated Hcy and the baseline or outcome UPDRS motor scores.CONCLUSIONSIn this cohort of early, untreated PD subjects, 1 in 4 had mildly elevated Hcy. Moderately elevated baseline Hcy levels correlated with lower baseline cognitive measures and greater rate of cognitive decline. Because B vitamin supplementation can lower Hcy levels, this data raises the possibility that prevention or early correction of mild to moderate hyperhomocyteinemia through vitamin supplementation may slow the onset of cognitive decline in PD.Support or Funding InformationMJFOX Foundation

A Mendelian Randomization Study of Plasma Homocysteine and Multiple Myeloma.

Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM (95% confidence interval (CI): 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).

Analysis of Homocysteine in Plasma of Rats Exposed to High-fat Diet and Chronic Unpredictable Mild Stress by LC/ESI-MS/MS

Context: Homocysteine (Hcy) is an amino acid that occurs in the body as an intermediate in the metabolism of methionine and cysteine. Hcyinplasma is a disease risk factor associated with both atherosclerosis and depression. The relation between Hcy balance and complication of atherosclerosis and depression remains unclear. Determination of Hcy in plasma is important and necessary for the research on comorbidities of atherosclerosis and depression. Objective: To establish an LC/ESI-MS/MS method for measuring plasma Hcy levels in rats and to compare plasma Hcy levels in rats exposed to high-fat diet, unpredictable mild stress or its combination. Materials and Methods: Forty rats were randomized into control group, high-fat group (HFD), chronic unpredictable mild stress group (CMS) and CMS+HFD group (n=10 in each group). 8 weeks later, the rats were sacrificed and plasma was collected for determining Hcy by LC/ESI-MS/MS. All data were analyzed by using SPSS13.0 software. Results: Compared to the plasma Hcy levels of control group, neither HFD group nor CMS group had statistical significance. However, CMS+HFD group showed a significantly higher level of plasma Hcy than the other three groups. Conclusions: Only when exposed to both high fat diets and chronic unpredictable mild stress, rats showed a remarkably elevated Hcy level in their plasma, however, when exposed alone to either high fat diet or chronic unpredictable mild stress, rats had a normal Hcy level in their plasma. Our findings indicate that Hcy is increased in comorbidity of atherosclerosis and depression. Keywords: Homocysteine, LC/ESI-MS/MS, chronic unpredictable mild stress, high-fat diet, atherosclerosis.

Tetradecylthiopropionic acid induces hepatic mitochondrial dysfunction and steatosis, accompanied by increased plasma homocysteine in mice.

BackgroundHepatic mitochondrial dysfunction plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methyl donor supplementation has been shown to alleviate NAFLD, connecting the condition to the one-carbon metabolism. Thus, the objective was to investigate regulation of homocysteine (Hcy) and metabolites along the choline oxidation pathway during induction of hepatic steatosis by the fatty acid analogue tetradecylthiopropionic acid (TTP), an inhibitor of mitochondrial fatty acid oxidation.MethodsMice were fed a control diet, or diets containing 0.3 %, 0.6 %, or 0.9 % (w/w) TTP for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, lipid and fatty acid composition in liver and plasma, one-carbon metabolites, B-vitamin status, carnitine and acylcarnitines were analyzed in plasma.ResultsLiver mitochondrial fatty acid oxidation decreased by 40 % and steatosis was induced in a dose dependent manner; total lipids increased 1.6-fold in animals treated with 0.3 % TTP, 2-fold with 0.6 % TTP and 2.1 fold with 0.9 % TTP compared to control. The higher hepatic concentration of fatty acids was associated with shortening of carbon-length. Furthermore, the inhibited fatty acid oxidation led to a 30-fold decrease in plasma carnitine and 9.3-fold decrease in acetylcarnitine at the highest dose of TTP, whereas an accumulation of palmitoylcarnitine resulted. Compared to the control diet, TTP administration was associated with elevated plasma total Hcy (control: 7.2 ± 0.3 umol/L, 0.9 % TTP: 30.5 ± 5.9 umol/L) and 1.4-1.6 fold increase in the one-carbon metabolites betaine, dimethylglycine, sarcosine and glycine, accompanied by changes in gene expression of the different B-vitamin dependent pathways of Hcy and choline metabolism. A positive correlation between total Hcy and hepatic triacylglycerol resulted.ConclusionsThe TTP-induced inhibition of mitochondrial fatty acid oxidation was not associated with increased hepatic oxidative stress or inflammation. Our data suggest a link between mitochondrial dysfunction and the methylation processes within the one-carbon metabolism in mice.

Prognostic Value of Elevated Homocysteine Levels in Korean Patients with Coronary Artery Disease: A Propensity Score Matched Analysis.

Background and ObjectivesWe sought to determine whether an elevated homocysteine (Hcy) level is associated with a worse prognosis in Korean patients with coronary artery disease (CAD).Subjects and MethodsA total of 5839 patients (60.4% male, mean age 61.3±11.2 years) with CAD were enrolled from 2000 to 2010 at Gangnam Severance Hospital. CAD was diagnosed by invasive coronary angiography. Laboratory values including Hcy level were obtained on the day of coronary angiography and analyses were performed shortly after sampling. Patients were divided into two groups according to their Hcy levels. Baseline risk factors, coronary angiographic findings, length of follow-up, and composite endpoints including cardiac death (CD) and non-fatal myocardial infarction (NFMI) were recorded. 1:1 propensity score matched analysis was also performed.ResultsOver a mean follow-up period of 4.4±2.5 years, there were 132 composite endpoints (75 CD and 57 NFMI) with an event rate of 2.3%. Mean Hcy level was 9.9±4.3 µmol/L (normal Hcy 7.9±1.5 µmol/L and elevated Hcy 13.9±5.1 µmol/L). Kaplan-Meier survival analysis showed an association of elevated Hcy level with worse prognosis (p<0.0001). In addition, a multivariate Cox regression analysis showed an association of elevated Hcy level with worse prognosis for both the entire cohort (hazard ratio [HR] 2.077, 95% confidence interval [CI] 1.467-2.941, p<0.0001) and the propensity score matched cohort (HR 1.982, 95% CI 1.305-3.009, p=0.001).ConclusionElevated Hcy level is associated with worse outcomes in Korean patients with CAD.

Plasma homocysteine levels are related to medium-term venous graft degeneration in coronary artery bypass graft patients.

Objective:Saphenous venous grafts (SVGs) are established choices for coronary artery bypass grafting (CABG); however, their lumen patency is limited. Our goal was to investigate the risk factors of SVG degeneration.Methods:Seventy-five patients (mean age, 57.5±10.4 years) with 133 SVG conduits who had cardiac catheterization ≥1 year after CABG were selected; follow-up period was 67.6±36.8 months. Patients were divided into 3 groups according to angiographic status at follow up [intact: <20% (n=23); narrowed: 20–99% (n=24); and occluded (n=28)]. Baseline clinical conditions were evaluated in relation to follow-up angiography. As onset date of chronic total occlusions is usually uncertain, they arise typically from thrombotic lesions; thus, their value in evaluation is limited.Results:There were no significant differences between the 3 groups in clinical parameters. Linear correlation analysis found significant (p<0.01) positive connection of SVG disease (luminal diameter reduction 20–99%) with C-reactive protein (CRP) and homocysteine (Hcy), as well as between CRP and Hcy. Multiple regression analysis showed plasma Hcy level to be significantly related to graft diameter reduction normalized to time elapsed until angiography in narrowed grafts: 1 µmol/L increase of Hcy was associated with 0.053%/month decrease in lumen diameter (p<0.01; R2=0.428); extrapolating: +10 µmol/L higher Hcy level during 5 years is associated with 32.1% lumen reduction.Conclusion:Medium- to long-term SVG degeneration is related to elevated plasma total Hcy in patients with sub-occlusive graft stenosis, while in cases with intact SVGs, the beneficial local flow conditions may protect the grafts from degeneration.

High Homocysteine Serum Levels as A Cause of Early and Massive Atherosclerosis: Vitamins B-6-9-12 Supplementation: More Shadows Than Lights

Folic acid and/or Vitamins B6-12 deficiency induces high-homocysteine (H-Hcy) serum levels for reduced activity of methylene-tetra hydro folate reductase (MTHFR). This metabolic derangement can be responsible for early and massive atherosclerosis, that could favour ischemic acute events. It can be assumed that vitamins’ supplementation, reducing the elevated Hcy serum concentration, could reduce atherosclerotic risk. In this review,we evaluated if, the reduction of the high Hcy values by the B-vitamins’ supplementation, is able to reduce the incidence of atherosclerotic events.Retrospective trials performed in patients already suffered of acute ischemic episodes, demonstrated that vitamins B6-9-12 supplementation was unable to reduce the incidence of new ischemic events, even if it lowers the high Hcy levels. On the contrary, perspective studies carried out in patients not previously suffered of cardiovascular acute events, evidenced that the vitamins’ supplementation significantly reduced both Hcy serum concentration and atherosclerotic risk. These conflicting results demonstrate that folic acid and vitamins B6/12 supplementation is effective in to reduce high Hcy serum concentration in patients with signs of previous atherosclerosis, but is unable to reduce the atherosclerotic risk. On the contrary, the supplementation is useful in to lower both high Hcy serum levels and atherosclerotic risk in patients without atherosclerotic marks. In addition, some experiences performed in this field demonstrated that these nutrients could favor some negative effects, as the growth of an unknown neoplastic mass, especially the cells of prostate cancer. Therefore, the supplementation with folates and other vitamins of B group can be performed cautiously in patients with increased Hcy serum concentration.

Impact of plasma homocysteinemia on contrast-induced nephropathy after percutaneous coronary intervention in patients with coronary syndrome

To explore the impact of plasma homocysteinemia(Hcy) on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) patients. Consecutive 684 ACS patients undergoing first PCI in our department between January 2013 and December 2014 were prospectively enrolled.Patients were divided into 2 groups according to the pre-procedural plasma Hcy level: high-Hcy group (Hcy≥10 μmol/L, n=404) and control group (Hcy<10 μmol/L, n=280). The CIN was defined as serum creatinine ≥ 44.2 μmol/L or 25% increase compared to baseline within 48-72 h after PCI.The baseline clinical data and the ratio of CIN were compared between the 2 groups.Multivariate logistic regression analysis was used to define the independent risk factors for CIN. CIN occurred in 133(19.4%) out of 684 enrolled patients, and the incidence of CIN was significantly higher in high Hcy group than in the control group (22.0%(89/404)vs. 15.7%(44/280), P=0.040). After adjusting the confounding factors, including age, acute myocardial infarction, co-morbidities(hypertension, diabetes mellitus, and old myocardial infarction), laboratory examination (level of cystatin C and uric acid), glomerular filtration rate, left ventricular ejection fraction, angiographic and procedural characteristics (3 diseased vessels, multiple stent implantation), treatment at admission (spironolactone, digoxin), multivariate logistic regression analysis showed that high Hcy was independently associated with the development of CIN (OR=1.70, 95%CI 1.60-2.64, P=0.021). Elevated Hcy prior PCI is an independent risk factor of CIN in ACS patients undergoing first PCI.

Hyperhomocysteinemia predicts renal function decline: a prospective study in hypertensive adults.

Hyper-homocysteinemia (HHcy) is associated with microalbuminuria and glomerular injury in general and diabetic populations. However, HHcy’s role in hypertensive patients was not studied. We investigated whether HHcy is an independent risk factor for renal function decline and development of chronic kidney disease (CKD) in hypertensive men and women. This was a community-based prospective cohort study of 2,387 hypertensive adults without CKD at baseline, with a mean follow-up of 4.4 years. Baseline and follow-up levels of plasma Hcy, folate, vitamin B12, blood pressure and other pertinent covariables were obtained. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/per 1.73 m2 and an eGFR decline rate >1 ml/min/per 1.73 m2/year. There was a graded association between Hcy tertiles and eGFR decline. Subjects in the 3rd tertile of Hcy levels had an accelerated rate of eGFR decline and an increased risk of incident CKD, as compared with those in the 1st tertile, after adjusting for age, gender, baseline diabetes, SBP, BMI, smoking, dyslipidemia, eGFR, folate and vitamin B12 levels. In conclusion, in this prospective cohort of Chinese hypertensive adults, elevated baseline plasma Hcy can serve as an independent biomarker to predict renal function decline and incident CKD.

DUAL EFFECT OF ATORVASTATIN ON ENDOTHELIUM

Objective: The objective of the study was to observe the effect of lipid loweringtherapy on homocysteine and TXA2 concentration in obese hyperlipidemic Sprague Dawleyrats. Design: Randomized Control Trial (RCT). Place and Duration of study: The study wasconducted in Department of Physiology and Centre for Research in Experimental and AppliedMedicine (CREAM), Army Medical College, Rawalpindi; and National Institute of Health (NIH)Islamabad over a period of 12 months. Methodology: Ninety healthy Sprague Dawley ratsdivided into three equal groups. Group I (n=30) were healthy controls, group II (n=30) weremade obese and group III (n=30) were obese treated (atorvastatin 10 mg/kg/day orally bygavage method for three weeks). Body weight was recorded thrice weekly, lipid profile wasmeasured by colorimetric method on microlab and homocysteine and TXA2 were measuredby Enzyme Linked Immunosorbant Assay. Results: Serum low density lipoproteins and TXA2decreased after three weeks of atorvastatin administration, elevated HCY concentration in obesehyperlipidemic rats however was not significantly affected. Conclusion: Atorvastatin apart fromlowering lipid levels in the body also reduces TXA2 concentration which is a vasoprotective.Elevated HCY concentration which is deleterious to the endothelium however is not affected.

Protein N-linked homocysteine is associated with recurrence of venous thromboembolism

BackgroundRecently, protein N-linked homocysteine (Hcy) has been measured in healthy subjects and patients with marked hyperhomocysteinemia. Since elevated total Hcy (tHcy) levels are associated with increased risk of venous thromboembolism (VTE), we aimed to investigate protein N-linked Hcy levels in patients with VTE. MethodsWe studied 200 consecutive patients with VTE (89 men, 111 women, aged from 17 to 83years), including 57 subjects with a subsequent episode of VTE (recurrent VTE) during 24months of follow-up. Protein N-linked Hcy was assayed using high-performance liquid chromatography with an on-column derivatization with o-phthaldialdehyde and fluorescence detection. ResultsThe median protein N-linked Hcy was 1.404μM (interquartile range [IQR] 0.859–2.066), while the median tHcy (IQR) was 9.1μM (6.8–11.2). In the whole group protein N-linked Hcy correlated only with C-reactive protein (CRP; r=0.44, p<0.0001). In patients with recurrent VTE protein N-linked Hcy correlated with C-reactive protein (r=0.43, p<0.0001), tHcy (r=0.42, p=0.001) and age (r=0.32, p=0.014), but not with thrombophilia, unprovoked VTE or the current anticoagulation. Hyperhomocysteinemia, defined as tHcy ≥15μM (n=14.7%), was not associated with higher protein N-linked Hcy. Patients with recurrent VTE had higher levels of protein N-linked Hcy compared to those who experienced a single episode of VTE (1.553μM, 1.157–2.445 vs. 1.27μM, 0.826–1.884; p=0.002). Multiple regression adjusted for potential confounders showed that the only independent predictor of protein N-linked Hcy in the upper quartile was CRP >3mg/L (odds ratio 3.04, 95% confidence interval 2.12–4.36, p<0.0001). ConclusionElevated protein N-linked Hcy concentrations, indicating enhanced protein homocysteinylation in vivo, characterize patients with recurrent VTE and this phenomenon is associated with enhanced inflammatory state.