Plasma Total Homocysteine Levels Research Articles

Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

The intake of ultra-processed foods and homocysteine levels in women with(out) overweight and obesity: The Rotterdam Periconceptional Cohort.

Today's diet consists of a substantial proportion of ultra-processed foods (UPF), especially in women with overweight and obesity in the reproductive period. High UPF intake results in an inadequate and unbalanced diet leading to derangements of several metabolic pathways detrimental to pregnancy and birth outcomes. Therefore, we aim to investigate whether UPF intake in the periconceptional period affects total homocysteine plasma levels (tHcy). 1532 participants were included from the prospective Rotterdam Periconceptional Cohort. UPF intake was calculated using Food Frequency Questionnaires including items classified as 4 in the Nova classification, and tHcy was measured by using liquid chromatography-tandem mass spectrometry system, with an interassay coefficient of variation of < 5.5%. Multivariable linear regression modeling was used and adjusted for covariates and significant interaction terms. Women with overweight or obesity showed significantly higher percentage of UPF intake (respectively, 50.3 and 51.3%) and higher tHcy (respectively, 6.6 and 6.3µmol/L, Kruskal-Wallis test; respectively, p < 0.001 and p = 0.04) compared to women with normal BMI (UPF intake: 46.8%, tHcy: 6.1µmol/L). A 10% higher intake of UPF was associated with an increase in tHcy (adjusted: β = 1.31, 95% CI = 0.38-2.23). Analysis stratified for BMI classification showed comparable associations in normal weight participants (adjusted: β = 1.07, 95% CI = 0.06-2.07); however, no significant association in participants with overweight (adjusted: β = 0.06, 95% CI = - 0.95-1.07) and obesity (adjusted: β = 1.70, 95% CI = - 0.52-3.92) was shown. This study showed that a higher intake of UPF is associated with increased tHcy. Better knowledge and awareness of the nutritional quality of the diet in the periconceptional period may contribute to 1-CM and subsequently improve pregnancy course and outcome. NTR4356, November 2010.

Association between Plasma Homocysteine Level and Atherogenic Index of Plasma among Hypothyroid Patients - A Case-Control Study

Introduction: Hypothyroidism is a common metabolic disorder in general population. Hypothyroidism is a commonly encountered health problem in Bangladesh and morbidity and mortality toll due to cardiovascular disease resulting from hypothyroidism is quite high. Hypothyroidism, dyslipidaemia and hyperhomocysteinemia are recognized risk factor for atherosclerosis and cardiovascular disease. Aim of the Study: The aim of this study was to evaluate the association between plasma Homocysteine level and atherogenic Index of plasma in patients with hypothyroidism. Methods: This was a case-control study and conducted in the Department of Biochemistry in cooperation with Department of Endocrinology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh during the period from January, 2012 to December, 2013. In our study, we included 60 newly diagnosed hypothyroid individuals as case and 60 euthyroid individuals as control. Result: In this study, most of the participants were female (62%) compared to male (38%) and we found the mean age of the case and control group was 34.31 ± 11.77 years and 32.42 ± 12.51 years. Mean serum homocysteine was found significantly higher in case group (19.00 ± 7.58 µmol/L) than control group (9.59 ± 1.91µmol/L).Mean AIP was found significantly higher in case (0.75 ± 0.27) than control (0.35 ± 0.20). We found 49 (81.67%) cases were within increased risk group of atherogenesis where as in control group it was 28 (46.67%).In present study, mild hyperhomocysteinemia was found in 80% cases and moderate hyperhomocysteinemia in 13.3% cases where as in control group it was 10% &amp; 0% respectively. Conclusion: In this study, we found that total plasma homocysteine level was significantly increased in recently diagnosed hypothyroidism and was normal in control groups. We also found that hypothyroidism is associated with high atherogenic index and hyperhomocysteinemia which causes premature atherosclerosis.

Methylenetetrahydrofolate reductase polymorphisms and elevated plasma homocysteine levels in small vessel disease.

Despite its public health importance, the causes of small vessel disease (SVD) are not fully understood. The presence of SVD in monogenic twins indicates the involvement of genetic factors in the pathogenesis of this disease. The purpose of this study was to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with SVD risk. Patients with SVD and matched controls were recruited from Tianjin Union Medical Center and Tianjin Huanhu Hospital. Clinical and laboratory data were collected. Plasma total homocysteine (tHcy) and folate levels were measured, and MTHFR rs1801133 (C677T) and rs1801131 (A1298C) single-nucleotide polymorphisms were genotyped. We analyzed potential associations among SVD and MTHFR polymorphisms, tHcy, and folate levels. Patients with SVD displayed significantly decreased plasma folate levels (Z=-3.537, p<.001) and increased tHcy levels (Z=4.910, p<.001) compared with controls. Significantly different plasma tHcy levels were associated with rs1801133 (χ2 =6.664, p=.036), and post hoc analysis indicated higher plasma tHcy levels in individuals carrying the TT allele compared with levels in those carrying the TC allele (Z=2.478, p=.013). No significant differences in tHcy levels were observed for rs1801131 alleles. The genotype and allele frequencies of rs1801133 were different between SVD and control groups (χ2 =9.378, p=.009). There was no significant difference in distributions of rs1801131 genotypes between the two groups, and multivariable logistic regression analysis showed that rs1801131 and rs1801133 were not significantly associated with the risk of SVD. Our study indicates that an elevated plasma tHcy level is independently associated with the development of SVD. Although MTHFR rs1801133 is linked to increased plasma homocysteine (Hcy) levels, it is not a risk factor for SVD. rs1801131 is not related to Hcy levels or SVD risk.

Hyperhomocysteinemia in Patients with Newly Diagnosed Primary Hypertension in Can Tho City, Vietnam.

Elevated levels of blood total homocysteine is one of the cardiovascular risk factors in hypertensive patients. Determine the prevalence of hyperhomocysteinemia and its associated factors in newly diagnosed primary hypertension patients. A cross-sectional descriptive study on 105 patients with newly diagnosed primary hypertension at Can Tho University of Medicine and Pharmacy Hospital from May 2017 to May 2018. Total homocysteine levels and related factors were collected at the study time. The mean plasma total homocysteine level was 16.24 ± 4.49 µmol/L. There were 78 patients with elevated plasma total homocysteine levels ≥15 µmol/L, accounting for 74.3% of all patients. Being elderly, gender, hypertension stage, and diabetes were factors associated with hyperhomocysteinemia (p &lt; 0.05). Total homocysteine levels were positively correlated with SBP, DBP, and age with r(SBP) = 0.696, r(DBP) = 0.585, and r(age) = 0.286. Research on the subpopulation of Vietnamese people shows that hyperhomocysteinemia is common in patients with newly diagnosed primary hypertension, and high blood total homocysteine levels are often related to age, sex, hypertension stage, and diabetes.

Effects of coffee supplementation on homocysteine and leptin levels: a systematic review and meta-analysis of clinical trials.

It has been reported that the consumption of antioxidant foods and beverages may benefit the development of cardiovascular risk factors. However, the impact of coffee consumption on some of these factors, such as homocysteine and leptin is controversial. Some clinical trials have suggested that coffee administration increases plasma total homocysteine levels, while others have found no significant changes in leptin concentrations. This study aimed to assess the effects of coffee supplementation on homocysteine and leptin concentrations in a meta-analysis of clinical trials. PubMed, Web of Science, Scopus, ClinicalTrials.gov, and Google Scholar databases were searched from inception to September 29, 2021. A fixed-effects model and the generic inverse variance weighting method were used for meta-analysis. The meta-analysis demonstrated that coffee administration significantly increases homocysteine levels (WMD: 0.55 µmol/L, 95% CI: 0.17, 0.93, p = 0.005, I2 = 0%) but has no significant changes in leptin concentrations (WMD: 1.34 ng/mL, 95% CI: -0.78, 3.45, p = 0.21, I2 = 0%). Additionally, the sensitivity analysis was robust for both homocysteine and leptin levels. The results of the present meta-analysis revealed that coffee supplementation raises serum homocysteine concentrations but has no effect on circulating leptin levels.

Reversal of neurovascular decoupling and cognitive impairment in patients with end-stage renal disease during a hemodialysis session: Evidence from a comprehensive fMRI analysis.

Neurovascular (NV) decoupling is a potential neuropathologic mechanism of cognitive impairment in patients with end-stage renal disease (ESRD). Hemodialysis improves cognitive impairment at 24 h post-dialysis, which suggests a potential neuroprotective effect of hemodialysis treatment on the brain. We investigated the effects of hemodialysis treatment on the reversal of NV decoupling associated with cognitive improvement. A total of 39 patients with ESRD and 39 healthy controls were enrolled. All patients were imaged twice during a dialysis session: before hemodialysis (T1pre-dialysis ) and at 24 h after dialysis (T2post-dialysis ). The healthy controls were imaged once. NV coupling was characterized based on correlation coefficients between four types of blood oxygen level-dependent signals and cerebral blood flow (CBF). A battery of neuropsychological and blood tests was performed before the imaging. Patients with ESRD showed improvements in memory and executive function at T2post-dialysis compared with that at T1pre-dialysis . At both T1pre-dialysis and T2post-dialysis , patients with ESRD had lower amplitude of low-frequency fluctuation (ALFF)-CBF coupling than healthy controls. Additionally, patients with ESRD had higher ALFF-CBF coupling at T2post-dialysis than at T1pre-dialysis . Higher memory scores, higher hemoglobin level, lower total plasma homocysteine level, lower systolic blood pressure variance, and lower ultrafiltration volume were associated with higher ALFF-CBF coupling in patients with ESRD after a hemodialysis session. These findings indicate that partial correction of anemia and hyperhomocysteinemia, stable systolic blood pressure, and fluid restriction may be closely linked to the reversal of NV decoupling and improvement in cognition in patients with ESRD.

Relationship between MMP-9 serum levels and tHcy levels and total imaging load and cognitive dysfunction

ObjectivesTo investigate the correlation and predictive value of serum matrix metalloproteinase-9 (MMP-9) level with cognitive dysfunction and total imaging load in patients with cerebral small vessel disease (CSVD). MethodsA total of 80 patients with CSVD who were admitted to the First Affiliated Hospital of Xinxiang Medical University between April 2019 and April 2020 were enrolled. All subjects underwent T1-weighted imaging (T1WI), T2WI, fluid-attenuated inversion recovery (FLAIR), diffusion weighted imaging (DWI), serum sample collection, and assessment of cognitive function at a specific time-point after admission. According to the results of the neuropsychological test, subjects were divided into cognitive dysfunction group (n=40) and normal cognitive function group (n=40). The total imaging load was estimated according to the neuroimaging findings. Serum MMP-9 level was measured by an enzyme-linked immunosorbent assay (ELISA) kit. Beside, serum MMP-9 level and total imaging load were compared between the two groups. ResultsSerum levels of MMP-9 and plasma total homocysteine (tHcy) were negatively correlated with cognitive function (P<0.05). Serum MMP-9 level was found as a significant factor for diagnosing cognitive impairment due to CSVD (area under the curve (AUC), 0.756; sensitivity and specificity were 97.5% and 75.0%, respectively). THcy level was also found as significant factor for diagnosing cognitive impairment due to CSVD (area under the curve (AUC), 0.727; sensitivity and specificity were 97.5% and 75.0%, respectively). ConclusionSerum MMP-9 level and tHcy level were significantly correlated with cognitive function in patients with CSVD. Serum MMP-9 level has a specific correlation with the total imaging load in patients with CSVD. It plays an important role in diagnosing cognitive impairment in patients with CSVD.

Correction to: Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation.

HomeJournal of the American Heart AssociationVol. 11, No. 19Correction to: Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation Open AccessCorrectionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessCorrectionPDF/EPUBCorrection to: Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation Originally published29 Sep 2022https://doi.org/10.1161/JAHA.121.020836Journal of the American Heart Association. 2022;11:e020836This article corrects the followingPlasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial FibrillationOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: September 29, 2022: Ahead of Print In the article by Ki‐Woong Nam et al, “Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation” which published online April 26, 2022 (J Am Heart Assoc. 2022;11:e022138. DOI: 10.1161/JAHA.121.022138) and was included in the May 3, 2022 issue of the journal, a correction was needed.The authors mistakenly provided an incorrect grant number in their Sources of Funding. The correct grant number from the National Research Foundation of Korea is NRF‐2019M3E5D1A01068991.The Sources of Funding statement now reads:“This study was partially supported by Korea University Grant (K1824521) and the National Research Foundation of Korea (NRF‐2019M3E5D1A01068991).”The authors regret the error.The online version of the article has been updated and is available here: https://www.ahajournals.org/doi/pdf/10.1161/JAHA.121.022138. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesPlasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial FibrillationKi‐Woong Nam, et al. Journal of the American Heart Association. 2022;11 October 4, 2022Vol 11, Issue 19Article InformationMetrics Copyright © 2022 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.https://doi.org/10.1161/JAHA.121.020836PMID: 36172962 Originally publishedSeptember 29, 2022 PDF download

Threshold effect of plasma total homocysteine levels on cognitive function among hypertensive patients in China: A cross-sectional study

BackgroundIncreased plasma total homocysteine (tHcy) is an influencing factor of cognitive impairment in the general population. However, studies on the relationship between the risk of cognitive impairment and plasma tHcy levels in patients with hypertension are limited. This study aimed to explore the association between plasma tHcy levels and cognitive function assessed by MMSE scores among hypertensive patients in China.MethodsA total of 9,527 subjects from the Chinese Hypertension Registry Study participated in this study. Plasma tHcy levels were quantified by high-performance liquid chromatography using a fluorescence detector. Cognitive assessment was performed using the Mini-Mental State Examination (MMSE). Linear regression models, two piecewise linear regression models, and smoothing curve fitting were applied to determine the relationship between plasma tHcy levels and cognitive function.ResultsThis analysis included 9,527 Chinese hypertensive adults. Based on the results of linear regression models, a negative relationship was identified between plasma tHcy levels and MMSE scores [beta coefficient (β) per standard deviation (SD) increase: −0.26, 95% confidence interval (CI) −0.35, −0.16, P &amp;lt; 0.001]. The fully adjusted smooth curve fitting presented a nonlinear between plasma tHcy levels and MMSE scores. The threshold effect analysis showed that the inflection point of tHcy was about 27.1 μmol/L. The effect size [β (95% CI)] per SD increase in plasma tHcy concentrations on MMSE scores was −0.93 (−1.24, −0.6) on the left side and −0.07 (−0.24, 0.10) on the right side of the inflection point (P-value for log-likelihood ratio (LLR) test was &amp;lt;0.001). Moreover, subgroup analyses revealed that sex could influence the negative association between plasma tHcy levels and MMSE scores up to a specific threshold (P-value for interaction &amp;lt;0.001). Linear regression models indicated that there was an enhanced inverse association between tHcy levels and MMSE scores in female patients with tHcy concentrations less than 26.9 μmol/L compared to male patients with tHcy concentrations less than 32.0 μmol/L.ConclusionsPlasma tHcy levels had a threshold effect on MMSE scores among hypertensive patients in China. Increased plasma tHcy levels were independently inversely associated with cognitive decline among hypertensive patients with tHcy concentrations &amp;lt;27.1 μmol/L.

Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria

To investigate the factors affecting phenotypes in the patients of methylmalonic acidemia combined with homocysteinemia cblC type with MMACHC c.609G>A homologous variant. A retrospective study on the clinical manifestations, complications, treatment, and outcome in 164 patients of cblC type with MMACHC c.609G>A homologous variant was conducted. The patients were diagnosed by biochemical and genetic analysis from January 1998 to December 2020. Among the 164 patients, 2 cases were prenatally diagnosed and began treatment after birth. They are 3 and 12 years old with normal physical and mental development. Twenty-one cases were diagnosed by newborn screening. Among them, 15 cases had with normal development. They were treated from the age of two weeks at the asymptomatic period. Six cases began treatment aged 1 to 3 months after onset. Their development was delayed. One hundred and forty-one cases were clinically diagnosed. Their onset age ranges from a few minutes after birth to 6 years old. 110 cases had early-onset (78.0%). 31 cases had late-onset (22.0%). Five of them died. 24 patients lost to follow-up. Of the 141 clinically diagnosed patients, 130 (92.2%) with psychomotor retardation, 69 (48.9%) with epilepsy, 39 (27.7%) with anemia, 30 (21.3%) had visual impairment, 27 (19.1%) had hydrocephalus, 26 (18.4%) had feeding difficulties, 7 (5.0%) with liver damage, and 5 (3.5%) with metabolic syndrome. The frequency of hydrocephalus and seizures was significantly higher in the early-onset group. The urinary methylmalonic acid increased significantly in the patients with epilepsy. During the long-term follow-up, the level of plasma total homocysteine in the seizure-uncontrolled group was significantly higher than that in the seizure-controlled group, the difference had a statistical significance (P<0.05). Most of the patients with MMACHC c.609G>A homozygous variant had early-onset disease, with a high mortality and disability rate. If not treated in time, it will lead to neurological damage, resulting in epilepsy, mental retardation, hydrocephalus, and multiple organ damage. Pre-symptomatic diagnosis and treatment are crucial to prevent irreversible neurological damage. Neonatal screening and prenatal diagnosis are important to improve the outcome of the patients.

Plasma Total Homocysteine Level Is Related to Unfavorable Outcomes in Ischemic Stroke With Atrial Fibrillation

BackgroundUnlike patients with stroke caused by other mechanisms, the effect of elevated plasma total homocysteine (tHcy) on the prognosis of patients with both ischemic stroke and atrial fibrillation (AF) is unknown. This study aimed to evaluate the association between tHcy level and the functional outcome of patients with AF‐related stroke.Methods and ResultsWe included consecutive patients with AF‐related stroke between 2013 and 2015 from the registry of a real‐world prospective cohort from 11 large centers in South Korea. A 3‐month modified Rankin Scale score ≥3 was considered an unfavorable outcome. Since tHcy is strongly affected by renal function, we performed a subgroup analysis according to the presence of renal dysfunction. A total of 910 patients with AF‐related stroke were evaluated (mean age, 73 years; male sex, 56.0%). The mean tHcy level was 11.98±8.81 μmol/L. In multivariable analysis, the tHcy level (adjusted odds ratio, 1.04; 95% CI, 1.01–1.07, per 1 μmol/L) remained significantly associated with unfavorable outcomes. In the subgroup analysis based on renal function, tHcy values above the cutoff point (≥14.60 μmol/L) showed a close association with the unfavorable outcome only in the normal renal function group (adjusted odds ratio, 3.10; 95% CI, 1.60–6.01). In patients with renal dysfunction, tHcy was not significantly associated with the prognosis of AF‐related stroke.ConclusionsA higher plasma tHcy level was associated with unfavorable outcomes in patients with AF‐related stroke. This positive association may vary according to renal function but needs to be verified in further studies.

Association of Homocysteine and Insulin Resistance with Increased Risk of Mortality in a Nondiabetic Population: Third National Health and Nutrition Examination Survey.

Background and Objective: The combined effect of insulin resistance (IR) and total plasma homocysteine (tHcy) levels on the risk of mortality in nondiabetic populations has rarely been studied. We aimed to examine the association of tHcy levels and IR with the risk of mortality in nondiabetic populations. Methods: This observational cohort study was based on data from the Third National Health and Nutrition Examination Survey (NHANES III) database (1999-2002). A generalized additive model based on the Cox proportional hazards models was applied to estimate the relationship of tHcy levels with all-cause and cardiovascular disease (CVD) mortality. Smooth curve fitting was used to analyze their dose-dependent relationship. Results: During 5.7 years of follow-up, a total of 146 (5.8%) deaths occurred, including 65 deaths from CVD among 2053 individuals aged 40-80 years. In the multivariable adjusted model, every 1-μM increment of the tHcy level was associated with a 15% increase in risk of all-cause mortality and 20% increase in risk of CVD mortality among participants with IR (adjusted HR [95% CI]: 1.15 [1.06-1.24] and 1.20 [1.04-1.38]). However, among participants without IR, an increase of 1 μM in the tHcy level was associated with a 6% increase in risk of all-cause mortality and 3% increase in risk of CVD mortality (adjusted HR [95% CI]: 1.06 [1.00-1.13] and 1.03 [0.92-1.16]). Conclusions: Homocysteine levels were associated with higher risk of all-cause and CVD mortality among individuals with IR than among those without IR in a nondiabetic population aged 40-80 years.

Epigenetic Upregulation of H19 and AMPK Inhibition Concurrently Contribute to S-Adenosylhomocysteine Hydrolase Deficiency-Promoted Atherosclerotic Calcification.

S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular disease; inhibition of SAH hydrolase (SAHH) results in SAH accumulation and induces endothelial dysfunction and atherosclerosis. However, the effect and mechanism of SAHH in atherosclerotic calcification is still unclear. We aimed to explore the role and mechanism of SAHH in atherosclerotic calcification. The relationship between SAHH and atherosclerotic calcification was investigated in patients with coronary atherosclerotic calcification. Different in vivo genetic models were used to examine the effect of SAHH deficiency on atherosclerotic calcification. Human aortic and murine vascular smooth muscle cells (VSMCs) were cultured to explore the underlying mechanism of SAHH on osteoblastic differentiation of VSMCs. The expression and activity of SAHH were decreased in calcified human coronary arteries and inversely associated with coronary atherosclerotic calcification severity, whereas plasma SAH and total homocysteine levels were positively associated with coronary atherosclerotic calcification severity. Heterozygote knockout of SAHH promoted atherosclerotic calcification. Specifically, VSMC-deficient but not endothelial cell-deficient or macrophage-deficient SAHH promoted atherosclerotic calcification. Mechanistically, SAHH deficiency accumulated SAH levels and induced H19-mediated Runx2 (runt-related transcription factor 2)-dependent osteoblastic differentiation of VSMCs by inhibiting DNMT3b (DNA methyltransferase 3b) and leading to hypomethylation of the H19 promoter. On the contrary, SAHH deficiency resulted in lower intracellular levels of adenosine and reduced AMPK (AMP-activated protein kinase) activation. Adenosine supplementation activated AMPK and abolished SAHH deficiency-induced expression of H19 and Runx2 and osteoblastic differentiation of VSMCs. Finally, AMPK activation by adenosine inhibited H19 expression by inducing Sirt1 (sirtuin-1)-mediated histone H3 hypoacetylation and DNMT3b-mediated hypermethylation of the H19 promoter in SAHH deficiency VSMCs. We have confirmed a novel correlation between SAHH deficiency and atherosclerotic calcification and clarified a new mechanism that epigenetic upregulation of H19 and AMPK inhibition concurrently contribute to SAHH deficiency-promoted Runx2-dependent atherosclerotic calcification.

EP258: Pre-analytical considerations are important in the pharmacological assessment of enzyme therapeutics

Enzyme therapeutics are distinct from other modalities as they have the potential to continue metabolizing their target analyte even after blood collection. This poorly characterized phenomenon is important as it may lead to an overestimation of the in vivo pharmacological effects of an enzyme therapeutic. With the recent development of highly effective metabolite lowering enzyme therapeutics, it is important to understand the impact of pre-analytical sample processing as a source of inaccurate metabolite measurements in pharmacological evaluation of both nonclinical and clinical studies. Pegzilarginase is a pegylated modified human arginase 1 enzyme in clinical development for Arginase 1 deficiency (ARG1-D). Given the potency of pegzilarginase, the potential for spurious measurements of plasma arginine levels was investigated. Continued metabolism of arginine was demonstrated ex vivo after blood draw leading to artefactually low arginine levels in normally processed plasma samples. These effects were ameliorated by the competitive arginase inhibitor nor-NOHA when added to the collection tube prior to blood collection. This approach has been adapted to ensure accurate measurement of plasma arginine in patients receiving pegzilarginase in clinical trials. Similarly, a recently developed engineered enzyme (AGLE-177), with novel specificity for homocysteine and homocystine has been shown to artefactually lower total homocysteine plasma levels ex vivo after blood collection. Mitigation of the effect, by adding an inhibitor to the blood collection tube, enabled accurate assessment of tHcy levels in non-clinical efficacy and toxicology studies. These studies highlight the need to consider continued enzymatic digestion of metabolites during the pre-analytical sample handling for in vivo pharmacological studies of enzyme therapeutics.

Role of plasma homocysteine levels and other associated factors with coronary artery disease among Palestinian patients in North Palestine: a case control study.

Introductioncoronary artery disease (CAD) is one of the leading causes of death worldwide, only two thirds of cases can be explained by CAD´s classical risk factors. There is an increase in attention to homocysteine as a causal of CAD. In Palestine, CAD is more common than that in regional surrounding areas. Coronary artery disease is considered the leading cause of death in the West Bank, according to Palestinian Ministry of health annual reports. The study was conducted to determine the level of homocysteine in individuals with no history of CAD and to determine the relationship between CAD and total homocysteine levels and classical risk factors of CAD.Methodsour study is a hospital-based case-control study. A sample size of 84 cases and 81 controls were included in the study.Resultsthere is a statistically significant increase in plasma total homocysteine level in cases compared to controls (P=0.04) with Odds ratio= 2. There is also a statistically significant association between plasma total homocysteine levels and age of 50 years and above and male gender among both study groups (P= 0.002 and 0.007, respectively). The study showed no significant association between plasma total homocysteine level and the CAD´s classical risk factors among the case group measured in the study, which are diabetes mellitus, hypertension, and smoking (P=0.5, 0.1, and 0.5, respectively).Conclusionthere is a significant difference in homocysteine levels between case and control groups. Coronary artery disease patients have double homocysteine levels compared to those healthy individuals with OR= 2. Healthy Palestinian individuals have a homocysteine level that is lower than that of regional communities. Homocysteine levels increase with advanced age and male gender. There is no significant relation between hyperhomocysteinemia and diabetes mellitus, hypertension, and smoking.

Relationship Between Plasma Total Homocysteine Levels and Mean Corrected TIMI Frame Count in Patients with Acute Myocardial Infarction.

ObjectiveTo explore the relationship between the plasma total homocysteine (tHcy) levels and slow coronary flow (SCF) measured by mean corrected TIMI frame count (CTFC) in patients with acute myocardial infarction (AMI).MethodsNinety-one patients with primary myocardial infarction were enrolled in this study. The quantitative measurement of coronary blood flow was performed using the mean CTFC method. Plasma tHcy levels were determined using enzymatic assay from venous blood samples. Multivariable linear regression models indicated were used to estimate the effect size (β) of plasma tHcy levels on mean CTFC levels.ResultsCompared with patients with the mean CTFC ≤23.61 frames per second (FPS) group, there were increased plasma tHcy levels in patients of the second, third and highest mean CTFC quartiles (P < 0.001). Linear regression models indicated that plasma tHcy levels were positively associated with mean CTFC levels (adjusted-β per SD increase: 1.96, 95% CI 1.20 to 2.73, P < 0.001). Compared to the tHcy ≤12.30 μmol/L group, the third and highest tHcy-quartile groups had higher mean CTFC levels (adjusted-β: 2.52, 95% CI 0.39 to 4.65, P = 0.023; adjusted-β: 5.07, 95% CI 2.98 to 7.16, P < 0.001, respectively; P for trend <0.001). Moreover, this positive relationship was modified by diabetes mellitus (P-value for interaction was 0.046).ConclusionWe found a positive relationship between plasma tHcy levels and mean CTFC levels in patients with AMI. Moreover, diabetes mellitus played an interactive role in this positive association between the plasma tHcy levels and mean CTFC levels.

Association Between Hyperhomocysteinemia Combined with Metabolic Syndrome and Higher Prevalence of Stroke in Chinese Adults Who Have Elevated Blood Pressure.

BackgroundHyperhomocysteinemia (HHcy) and metabolic syndrome (MS) are established cardiovascular risk factors of stroke and are frequently associated with hypertension. However, studies on the association between HHcy combined with MS and stroke risk in hypertensive patients were absent.Material/MethodsIn 14 059 selected participants with elevated blood pressure, we assessed the prevalence of the MS and stroke. We defined HHcy as plasma total homocysteine >15 μmol/L. MS was defined according to the Chinese Diabetes Society (CDS) criterion. Multivariable analysis was used to examine the association of HHcy or (and) MS with stroke risk in different models.ResultsThe prevalence rates of HHcy and MS were 49.96% and 42.21%, respectively. Patients with stroke had higher plasma total homocysteine levels and a higher prevalence of MS (P<0.001). Multivariable analyses indicated that HHcy and MS are independently associated with higher prevalence of stroke (adjusted-odds ratio (OR): 1.36, 95% CI 1.17 to 1.58, P<0.001; adjusted-OR: 1.68, 95% CI 1.44 to 1.96, P<0.001, respectively). Those with combined HHcy and MS had higher odds of stroke than those with isolated HHcy or MS (adjusted-OR: 1.78, 95% CI 1.47 to 2.15, P<0.001; adjusted-OR: 1.39, 95% CI 1.13 to 1.70, P=0.002, respectively).ConclusionsHHcy combined with MS was associated with higher prevalence of stroke in Chinese adults with elevated blood pressure.

Association of Elevated Plasma Total Homocysteine With Dementia With Lewy Bodies: A Case-Control Study.

Background: Elevated plasma total homocysteine (tHcy) level, a known risk factor for vascular disease, is reported to be an independent risk factor for cognitive impairment and Alzheimer’s disease (AD) in most studies. tHcy may also be associated with dementia with Lewy bodies (DLB).Objective: To investigate the association between plasma tHcy levels and DLB or AD.Methods: This is a case-control study including 132 DLB patients, 264 AD patients, and 295 age-matched healthy controls. We used multivariate logistic regression model to analyze the data with adjustments for confounding variables.Results: The highest tHcy tertile (>13.9 μmol/L) was significantly independently associated with DLB [adjusted odds ratio (OR): 4.65, 95% confidence interval (CI): 1.95–11.10, P = 0.001] and AD (adjusted OR: 1.82, 95% CI: 1.02–3.23, P = 0.041) compared to the lowest tertile (<10.7 μmol/L). The cumulative frequency plots showed a shift in the distribution of the tHcy concentrations to higher values in patients with DLB compared to AD. The mean tHcy levels were stable and not altered by the duration of cognitive impairment prior to the collection of blood samples from DLB patients.Conclusion: Elevated plasma tHcy levels were independently associated with DLB, and the association was stronger for DLB than for AD. The lack of a relationship between tHcy levels and symptom duration may refute these observed associations being a consequence of DLB, and future longitudinal studies will be required to confirm whether tHcy plays a causative role in DLB.

Changes in Total Homocysteine and Glutathione Levels After Laparoscopic Sleeve Gastrectomy in Children with Metabolic-Associated Fatty Liver Disease.

Paediatric obesity is a well-known risk factor for metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate the effects of laparoscopic sleeve gastrectomy (LSG) on the levels of total homocysteine (tHcy) and total glutathione (tGSH) plasma levels in children with MAFLD. Twenty-four children with severe obesity who underwent LSG were included in the study. The metabolic parameters, systemic inflammatory markers, one-carbon metabolism products, ultrasound and histological improvement were evaluated at baseline (T0M) and after 12months from LSG (T12M). The patients exhibited a significant amelioration of several metabolic parameters at T12M. A significant reduction of steatosis was observed at ultrasound (from 72.7% of moderate-severe grade to 0% severe steatosis), accompanied by a statistically significant improvement of ballooning, portal and lobular inflammation and fibrosis. A statistically significant decrease of tumour necrosis factor circulating levels was also observed (T0M median = 290.3, IQR = 281.0-317.0pg/mL; T12M median = 260.4, IQR = 240.0-279.0pg/mL; p < 0.0001). After 12months from LSG, a significant increase of mean plasma levels of tHcy(T0M mean = 15.7 ± 4.1μmol/L; T12M mean = 21.1 ± 9.3μmol/L; p = 0.0146) was also observed. The increase of tHcy showed no causal link with the improvement of MAFLD-related inflammatory, metabolic and histological pattern. LSG in children with obesity induces an improvement of MAFLD-related metabolic derangement and liver damage, but also a mild hyperhomocysteinemia that should be avoided to prevent cardiovascular risk.