Elevated Homocysteine Levels Research Articles

Vitamin B12 deficiency and hyperhomocysteinemia: A description of two cases with thrombosis

Abstract: Elevated homocysteine levels are associated with venous and arterial thrombosis. This report describes two patients with low vitamin B12 levels due to pernicious anaemia and elevated homocysteine levels, one of whom presented with an arterial thrombosis (cerebrovascular event) and another with venous thrombosis (deep vein thrombosis) without any other apparent cause for their presentation. Although not routinely recommended, it may be of value to screen patients with unexplained arterial or venous thrombotic events for elevated homocysteine levels. However, the paradox remains, that while hyperhomocysteinemia is associated with an increased risk of thrombosis, therapeutic strategies that lower homocysteine levels do not reduce the risk of thrombotic events.

ДОСЛІДЖЕННЯ ПОКАЗНИКІВ ОКСИДАТИВНОГО СТРЕСУ В НИРКАХ СТАТЕВОНЕЗРІЛИХ ЩУРІВ З ГІПЕРГОМОЦИСТЕЇНЕМІЄЮ

Purpose: Hyperhomocysteinemia in children can develop as a result of genetic defects, endocrine abnormalities or under the influence of dietary factors. An elevated level of homocysteine is considered a risk factor for the progression of chronic kidney disease. The aim of the work was to investigate the indicators of oxidative stress in the homogenate of the kidneys of immature rats in control and with hyperhomocysteinemia. Methods: The concentration of reduced and oxidized glutathione, the activity of superoxide dismutase, catalase and nitric oxide synthase were determined. The model of hyperhomocysteinemia was reproduced on one-month-old male rats, which were kept on a standard vivarium diet. The experimental group was intragastrically administered by D,L-thiolactone homocysteine hydrochloride in a 1% starch solution at a dose of 200 mg/kg of body weight 1 per day for 8 weeks. The corresponding volume of 1% starch solution was injected into the control group of animals. The activity of superoxide dismutase, catalase and nitric oxide synthase were determined spectrophotometrically. Concentration of reduced and oxidized glutathione by fluorometric method. Results: It was established that upon hyperhomocysteinemia the concentration of reduced glutathione, the activity of superoxide dismutase, catalase, and nitric oxide synthase was decreased against the background of an increase in the concentration of oxidized glutathione in the homogenate of the kidneys of immature rats. Conclusions: The obtained results indicate that in the kidneys of immature rats, the development of oxidative stress occurs in the direction characteristic of adult animals. The obtained results indicate that in the kidneys of immature rats the development of oxidative stress resembles the adult animals. The obtained results showed a decrease in the concentration of reduced glutathione and the activity of antioxidant defense enzymes which may indicate the development of pathological processes in the kidneys

Suicidal ideation in a sample with a first-episode of restrictive eating disorders: The role of biomarkers

This study investigates the associations between the presence of suicidal ideation (SI), depressive symptoms and potential biomarkers in a sample with treatment-naïve first episode restrictive eating disorder The observational study included 77 patients and 53 controls matched by age and socioeconomic status. We used the Beck Depressive Inventory focusing particularly on item 9, which measure the severity of SI. We found high rates of SI (40.8%) and depression (52.9%). Serum ​​levels of homocysteine were significantly higher among patients who reported SI compared with patients without SI (t = 2.47; p = .016; d = 0.595). Greater depressive symptoms were significantly correlated to lower levels of vitamin B12 (t = 2.08; p = .041; d = -0.504) and folic acid (U = 403.5; p = .015; d = -0.039). Serum levels of homocysteine were inversely correlated to those of vitamin B12 ​​(rho = -0.310; p < 0.01) and folic acid (rho = -0.329; p < 0.01). The results may not be generalizable to patients with purgative behaviors or males. Our study suggests that patients with restrictive eating disorder seem to have a higher rate of SI and depressive symptoms in the early stages of the disease. These results show the importance of affective symptoms and their role in the pathogenesis and illness outcome. Moreover, the evidence from this study suggest that elevated homocysteine ​​levels could be related to the presence of SI. Therefore, early detection and treatment of these patients could lead to an improvement in their prognosis.

A cross-sectional study of comparison of elevated levels of serum Homocysteine in intracranial and extracranial atherosclerotic stenosis groups.

Introduction: The primary goal of this study was to compare serum homocysteine levels in acute ischemic strokes caused by extracranial atherosclerotic stenosis (ECAS) and intracranial atherosclerotic stenosis (ICAS)groups in order to see if there was a link between elevated serum homocysteine levels and ICAS. Methodology: The present study was a cross-sectional study done by the department of neurology at a tertiary level hospital in Mumbai. Various clinical, radiological &amp; laboratory parameters including serum Homocysteine were compared between patients with ECAS and ICAS stroke. Results: The study enrolled a total of 150 patients, with 110 in the ECAS group and 40 in the ICAS group. We observed that mean serum Homocysteine levels were 2.42 µg/ml in the ECAS group and 4.88 µg/ml in the ICAS group (p=0.01). High serum Homocysteine levels were more common in the ICAS group than in the ECAS group (55 percent versus 33.6 percent, p = 0.01). The lipid profile was found to be similar in the two study groups, except for low HDL, which was observed in 70 (64%) of the ECAS patients as compared to 17 (43%) of the ICAS (p-value &lt; 0.05). There was no statistical difference in the caparison of demographic and other risk factor profiles between ECAS and ICAS patients. Conclusions: High serum Homocysteine levels were found to be more common in the ICAS group than in the ECAS group.

Can &amp;lt;I&amp;gt;Plasmodium falciparum&amp;lt;/I&amp;gt; Induce Homocysteinemia in Malaria Patients?

Background: Plasmodium falciparum has developed elaborate strategies to survive in the hostile intracellular environment of the infected host cell, including resistance to oxidative stress. Cysteine is a metabolic product of homocysteine and a precursor of the antioxidant glutathione used by Plasmodium falciparum to escape harmful oxidation. Objectives: In the present study we aimed to assess whether Plasmodium falciparum can induce homocysteinemia in malaria patients of Burkina Faso. Methods: Eighty-five (85) individuals including 25 affected by severe malaria, 44 by simple malaria, and 12 negative controls for P. falciparum infection were included in the present study. An enzymatic assay of plasma homocysteinemia was performed using the Homocysteine Enzymatic Assay reagent (ref 05385415 190) on the Roche/ Hitachi Cobas c. Results: The results of the present study show that the mean plasma homocysteine concentrations were 15.1 ± 8.4 μmol/L among patients with severe malaria, 14.0 ± 6.0 μmol/L in patients with uncomplicated malaria, and 12.6 ± 4.1 μmol/L in negative controls for malaria parasite. Conclusions: Our findings suggest high homocysteinemia in malaria patients, especially in those with severe malaria. Monitoring homocysteinemia in the latter group will be useful to avoid complications when an elevated plasma level of homocysteine is a known risk factor for cardiovascular diseases.

Genetic expression changes and pathologic findings associated with hyperhomocysteinemia in human autopsy brain tissue.

Vascular contributions to cognitive impairment and dementia (VCID) are a leading cause of dementia. An underappreciated, modifiable risk factor for VCID is hyperhomocysteinemia (HHcy), defined by elevated levels of plasma homocysteine, most often due to impaired B vitamin absorption in aged persons. Studies aimed at identifying neuropathologic features and gene expression profiles associated with HHcy have been lacking. A subset of research volunteers from the University of Kentucky Alzheimer's Disease Research Center longitudinal cohort came to autopsy and had ante mortem plasma homocysteine levels available. Brain tissue and blood plasma drawn closest to death were used to measure homocysteine and related metabolites in the current pilot study. Genetic expression profiles of inflammatory markers were evaluated using the Human Neuroinflammation NanoString panel. Further analyses included an evaluation of plasma homocysteine effects on amyloid beta, tau, ionized calcium-binding adaptor molecule 1, and glial fibrillary acidic protein immunohistochemistry in the frontal and occipital cortices. Analytes and other study outcomes were evaluated in relation to ante mortem HHcy status: We identified 13 persons with normal ante mortem plasma homocysteine levels (<14µmol/L) and 18 who had high plasma homocysteine levels (≥14µmol/L). Participants with HHcy demonstrated increased levels of several plasma homocysteine cycle metabolites such as total cysteine, S-adenosyl-homocysteine, cystathionine, and choline. Inflammatory gene expression profiles showed a general downregulation in the setting of elevated plasma homocysteine. HHcy was associated with more and longer microglial processes, but smaller and fewer astrocytes, especially in participants of older age at death. HHcy in older participants was also associated with occipital cortex microhemorrhages and increased severity of atherosclerosis throughout the cerebral vasculature. Increased plasma homocysteine and older age were associated with the downregulation of inflammatory gene expression markers in association with significant glial and vascular pathology changes. Impaired immune function is a plausible mechanism by which HHcy increases cerebrovascular damage leading to impaired cognitive function.

THE ROLE OF DIET IN MULTIPLE SCLEROSIS.

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), characterized by chronic inflammation associated with autoimmune damage to myelin and axons leading to neurodegeneration. Although the etiology is not fully understood, some factors that increase the risk of disease have been identified. One of the key elements of multidisciplinary approach to the management of MS is a properly balanced diet, e.g. Swank diet. Its main assumption is to reduce the supply of animal fats in favor of fats of plant origin, which contain polyunsaturated fatty acids omega-3. One of the factors influencing the course of the disease is vitamin D deficiency. In 80-90% it is synthesized by exposure to the sun, while the other 10-20% may be supplied with ingested food. Although elevated plasma homocysteine levels have been demonstrated in MS patients, there is no need to modify the supply of B vitamins. Further studies are necessary to show the correlation between the supply of B vitamins and the course of the disease. Due to the antioxidant effect, it is recommended to include products that are sources of vitamin A, E and C, glutathione, coenzyme Q10. It is also beneficial to include compounds from the polyphenol group: quercetin, resveratrol and curcumin. Through proper nutrition model it is also possible to reduce side effects of applied medications, such as constipation, what improves patients' quality of life. Diet therapy is a key element supporting pharmacotherapy in patients with multiple sclerosis.

Telomere length and vitamin B12.

Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for "biological aging." Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.

Ketamine as an Adjunct for Treatment of Methotrexate-induced Neurotoxicity.

Methotrexate (MTX) is used in the treatment of several childhood cancers and is a main component of the treatment regimen for osteosarcoma. MTX has been linked with side effects of varying severity; headaches, nausea, emesis, lethargy, blurred vision, aphasia, hemiparesis, paresis, convulsions, leukoencephalopathy, and arachnoiditis are symptoms of MTX toxicity. MTX-induced neurotoxicity can occur in up to 15% of patients receiving high-dose MTX. The effects may be transient but can have life-threatening implications, sometimes requiring intubation for respiratory support and airway protection. Elevated homocysteine levels in the cerebrospinal fluid are documented in cases of MTX-induced neurotoxicity; dextromethorphan is used as an initial treatment for MTX-induced neurotoxicity as it works as a noncompetitive antagonist for the N-methyl D-aspartate receptors and suppresses homocysteine activity. In severe cases requiring intubation, medications for sedation are utilized. Ketamine is also an N-methyl D-aspartate receptor antagonist, and as such, may be considered as an optimal treatment choice when sedation is required. We describe the use of ketamine in a pediatric patient with MTX-induced neurotoxicity. The use of ketamine in the treatment of MTX-induced neurotoxicity has not been described in the literature.

Застосування екстракорпоральних методів детоксикації для елімінації метотрексату

Описаний клінічний випадок 12-річної дитини з остеосаркомою лівої малогомілкової кістки, Т1N0M0G3, яка отримувала лікування високодозовим метотрексатом 12 г/м2. Внаслідок затримки елімінації метотрексату в дівчинки розвинулась гостра печінкова недостатність. У пацієнтки рівень АЛТ підвищувався до 4790 Од/л, АСТ — до 4320 Од/л, що свідчить про загрозливе для життя гостре ураження печінки. При цьому не відмічалися коагулопатія, значне підвищення рівня білірубіну та печінкова енцефалопатія. Повній картині гострої печінкової недостатності вдалося запобігти завдяки своєчасному застосуванню еферентної терапії. Пацієнтка отримувала внутрішньовенну гідратаційну терапію та олужнення сечі в об’ємі 3000 мл/м2/добу розчинами 5% глюкози в комбінації з 20 ммоль NaHCO3/л та 20 ммоль розчину KCl/л. При цьому діурез пацієнтки становив більше ніж 600 мл/м2/6 годин. Крім того, застосовувалась антидотна терапія кальцію фолінатом. У даному випадку ми використали тривалу вено-венозну гемодіафільтрацію апаратом Prismaflex. Після першого проведеного сеансу, що тривав протягом 78 годин, відмічалось повторне зростання концентрації метотрексату в крові та збільшення рівнів АЛТ, АСТ, що свідчить про великий об’єм розподілу метотрексату та потребу в тривалій терапії екстракорпоральними методами. Тому сеанс тривалої вено-венозної гемодіафільтрації був продовжений. Після ще 78 годин проведення тривалої вено-венозної гемодіафільтрації відмічались відсутність повторного зростання показників рівня метотрексату в крові та нормалізація рівнів трансаміназ та загального білірубіну. Додатково в пацієнтки були досліджені рівень гомоцистеїну на предмет гіпергомоцистеїнемії, а також 4 гени, які також визначають схильність до гіпергомоцистеїнемії, — метилентетрагідрофолат редуктаза MTHFR C677T, A1298C, метіонін синтетаза MTRR та MTR. Підвищений рівень гомоцистеїну, а також гетерозиготність даних генів свідчать про сповільнення виведення метотрексату або про повну затримку його виведення. У даному випадку результати даних досліджень були негативними. Висновки. Даний клінічний випадок свідчить про ефективність застосування тривалої вено-венозної гемодіафільтрації в комбінації з внутрішньовенною гідратацією, олужненням сечі та антидотною терапією при токсичному впливі на печінку високодозового метотрексату на тлі уповільненої екскреції.

Role of mutations in MTHFR gene and hyperhomocysteinemia in occurrence of ischemic stroke

The objective of the study is review and analyze scientific publications devoted to the problems of stroke, its relationship with the most common mutations in the MTHFR gene and their individual allelic variants and serum homocysteine levels.Materials and methods. Analyzing foreign and domestic publications, the relationship of the strongest mutations in the MTHFR gene with an increase in the level of serum homocysteine, which is a predictor of the development of vascular accidents, including acute circulatory disorders of the brain, was revealed.Results. Stroke is a socially significant disease. All risk factors for acute cerebral stroke are subdivided into modifiable and non-modifiable. To a non-modifiable factor that predisposes to the development of ischemic and hemorrhagic stroke, hereditary factors, including genetic mutations in a number of genes. MTHFR is a genome carrying individual allelic variants that can affect the level of homocysteine in blood serum, causing it to increase, and hyperhomocysteinemia, according to a number of studies, is a likely predictor of diseases of the cardiovascular system, including severe cerebrovascular accidents. At the same time, a large number of studies use the services of the protective role of reducing the elevated level of serum homocysteine using various forms of folic acid and B vitamins. The authors of the article attempted to process, analyze and summarize the data of modern research issues on the topic under consideration.Conclusions. The relationship between the occurrence of ischemic and hemorrhagic stroke and the most common mutations in the MTHFR gene has been revealed. Hyperhomocysteinemia, separate and developing as a result of these mutations, is an independent risk factor for the development of acute cerebral ischemia. Normalization of elevated serum homocysteine levels is required for all patients as stroke prevention, and includes not only the use of foods enriched with folic acid, but also pharmacological correction of folates and B vitamins.

The Role of Folic Acid in Stroke Prevention

Stroke is one of the most serious health problems faced today. This is because a sudden stroke can cause physical and mental disabilities that can interfere with a person's productivity and can even cause sudden death. Stroke can be divided into two, namely hemorrhagic stroke and non-hemorrhagic stroke. Hemorrhagic stroke is a stroke that occurs due to damage to blood vessels in the brain. While non-hemorrhagic stroke, also known as ischemic stroke, occurs when the blood supply to the brain is interrupted or stopped. About 80% of the most common strokes are caused by an ischemic stroke. One of the causes of ischemic stroke due to atherosclerotic plaque. Elevated levels of homocysteine ??in the blood (hyperhomocysteinemia) can lead to chronic inflammation of the blood vessels that triggers the formation of atherosclerotic plaques and causes blockage of blood flow. Folic acid is a type of water-soluble vitamin and can play a role in preventing stroke. Folic acid can act as an antihomocysteine ??so that it can prevent the formation of atherosclerotic plaques which is one of the risk factors for stroke

Effect of long-term chronic hyperhomocysteinemia on retinal structure and function in the cystathionine-β-synthase mutant mouse

Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine β-synthase (CBS). Cbs+/- mice have a ∼two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs+/- mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs+/- and Cbs+/+ (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured ∼0.36c/d for mice at 20 months in Cbs+/- and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs+/- and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed ∼5 RGCs/100 μm retinal length in both Cbs+/- and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs+/- and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms.

Relationship between homocysteine levels and post-stroke cognitive impairment in female and male population: from a prospective multicenter study.

ABSTRACTBackground and Objectives:To investigate the relationship between homocysteine levels and post-stroke cognitive impairment (PSCI) in Chinese female and male populations with minor acute ischemic stroke or transient ischemic attack.Materials and methods:A total of 1070 participants with clinically confirmed acute minor ischemic stroke or transient ischemic attack and baseline homocysteine information from a nationwide multicenter prospective registry study in China were included in this study. Of these, 919 patients had cognitive assessments at 3-month follow-ups and 584 participants had cognitive assessments at 12-month follow-ups. The incidence of PSCI was defined as a Montreal Cognitive Assessment score ≤22. The differences in homocysteine levels and the incidence of PSCI were compared between female and male populations. Relationships between homocysteine levels and the incidence of PSCI in female and male populations were analyzed using multiple logistic regression, respectively.Results:Females had lower baseline homocysteine levels than males. Compared to males, females had lower education levels, lower rates of smoking and alcohol intake, and higher rates of diabetes and hypertension. No relationship was observed between elevated homocysteine level and 3-month PSCI incidence in either females or males. After adjusting the confounders, elevated baseline homocysteine significantly increased the 12-month PSCI risk (odds ratio 3.28, 95% confidence interval 1.47–7.34, P = 0.004) in females, but not in males (odds ratio 0.86, 95% confidence interval 0.49–1.49, P = 0.586).Conclusion:Elevated homocysteine levels increased the 12-month PSCI risk in females, but not in males with minor acute ischemic stroke or transient ischemic attack.

Endothelial Dysfunction and Hyperhomocysteinemia-Linked Cerebral Small Vessel Disease: Underlying Mechanisms and Treatment Timing.

Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.

Hyperhomocysteinemia Induces Rat Memory Impairment Via Injuring Hippocampal CA3 Neurons and Downregulating cAMP Response Element-Binding Protein (CREB) Phosphorylation.

Accumulated evidence demonstrated that an elevated plasma homocysteine level, hyperhomocysteinemia, induced cognitive impairment in animals, elderly and the patients with neurodegenerative diseases. To date, the underlying cellular and molecular mechanisms by which hyperhomocysteinemia induces cognitive impairment has not been clearly defined. The purpose of this study was to investigate the possible cellular and molecular mechanisms behind hyperhomocysteinemia signaling in rat memory impairment. The results from this study demonstrated that hyperhomocysteinemia induced neuronal damage and loss in hippocampal CA3 region and downregulated the cAMP response element-binding protein (CREB) phosphorylation. The findings of this study provide evidence that hyperhomocysteinemia induces rat memory impairment via injuring hippocampal CA3 neurons and downregulating CREB phosphorylation.

Abstract 17117: Hyperhomocysteinemia Associated St Elevation Myocardial Infarction In A Young Male

Case Presentation: A 24-year-old male with a medical history of Crohn’s on mesalamine presented to the emergency room with crushing substernal chest pain at rest. Electrocardiogram revealed ST elevations in Lead V2-V5 (Figure-1a). He was taken emergently to the catheterization laboratory and had 100% thrombotic occlusion of his proximal left anterior descending coronary artery (LAD) (Figure-1b). Intravascular ultrasound (IVUS) confirmed the presence of soft atheromatous lipid-rich plaque in the proximal LAD with heavy thrombus burden (Figure-1c/d). He underwent aspiration thrombectomy and IVUS guided percutaneous coronary intervention with a 4.5 mm x 32 mm drug-eluting stent. Echocardiogram revealed an akinetic anterior wall with an ejection fraction of 35% without a patent foramen ovale. Hypercoagulable workup was initiated and showed a significantly elevated homocysteine level of 84.4 umol/L (normal:3.5-10.4). Family history, drug screen, hemoglobin A1C, and lipid profile were unremarkable. Discussion: The differential diagnosis in a young male presenting with a STEMI includes thromboembolism versus plaque rupture. IVUS showed clear evidence of a lipid-rich plaque demonstrating premature atherosclerotic vascular disease rather than a thromboembolic event. His most striking risk factor was hyperhomocysteinemia with a level of 84.4 umol/L. Elevations in homocysteine plasma concentration has been identified as an independent risk factor for atherosclerosis due to its atherogenic and prothrombotic properties. To date lowering homocysteine levels with folate and additional therapies have not shown to reduce the risk of coronary disease. Our case stresses the importance of intravascular imaging, especially in atypical cases such as a young male presenting with a STEMI to differentiate plaque rupture versus thromboembolism. Further studies are needed to identify risk modifying therapies for hyperhomocysteinemia associated vascular disease.

CRIF1 Deficiency Increased Homocysteine Production by Disrupting Dihydrofolate Reductase Expression in Vascular Endothelial Cells.

Elevated plasma homocysteine levels can induce vascular endothelial dysfunction; however, the mechanisms regulating homocysteine metabolism in impaired endothelial cells are currently unclear. In this study, we deleted the essential mitoribosomal gene CR6 interacting factor 1 (CRIF1) in human umbilical vein endothelial cells (HUVECs) and mice to induce endothelial cell dysfunction; then, we monitored homocysteine accumulation. We found that CRIF1 downregulation caused significant increases in intracellular and plasma concentrations of homocysteine, which were associated with decreased levels of folate cycle intermediates such as 5-methyltetrahydrofolate (MTHF) and tetrahydrofolate (THF). Moreover, dihydrofolate reductase (DHFR), a key enzyme in folate-mediated metabolism, exhibited impaired activity and decreased protein expression in CRIF1 knockdown endothelial cells. Supplementation with folic acid did not restore DHFR expression levels or MTHF and homocysteine concentrations in endothelial cells with a CRIF1 deletion or DHFR knockdown. However, the overexpression of DHFR in CRIF1 knockdown endothelial cells resulted in decreased accumulation of homocysteine. Taken together, our findings suggest that CRIF1-deleted endothelial cells accumulated more homocysteine, compared with control cells; this was primarily mediated by the disruption of DHFR expression.

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.

Long-term functional correction of cystathionine β-synthase deficiency in mice by adeno-associated viral gene therapy.

Cystathionine β-synthase (CBS) deficiency is a recessive inborn error of sulfur metabolism characterized by elevated blood levels of total homocysteine (tHcy). Patients diagnosed with CBS deficiency are currently treated by a combination of vitamin supplementation and restriction of foods containing the homocysteine precursor methionine, but the effectiveness of this therapy is limited due to poor compliance. A mouse model for CBS deficiency (Tg-I278T Cbs-/- ) was used to evaluate a potential gene therapy approach to treat CBS deficiency utilizing an AAVrh.10-based vector containing the human CBS cDNA downstream of the constitutive, strong CAG promoter (AAVrh.10hCBS). Mice were administered a single dose of virus and followed for up to 1 year. The data demonstrated a dose-dependent increase in liver CBS activity and a dose-dependent decrease in serum tHcy. Liver CBS enzyme activity at 1 year was similar to Cbs+/- control mice. Mice given the highest dose (5.6 × 1011 genomes/mouse) had mean serum tHcy decrease of 97% 1 week after injection and an 81% reduction 1 year after injection. Treated mice had either full- or substantial correction of alopecia, bone loss, and fat mass phenotypes associated with Cbs deficiency in mice. Our findings show that AAVrh.10-based gene therapy is highly effective in treating CBS deficiency in mice and supports additional pre-clinical testing for eventual use human trials.