Hyperhomocysteinemia as a Risk Factor for Intracranial Aneurysms: A Case-Control Study.

OBJECTIVE: Homocysteine, an amino acid derived from methionine metabolism, has gained great importance as an important risk factor for cardiovascular diseases as the result of its thrombogenic properties and endothelial injury association. However, its role in the etiology and screening of intracranial aneurysms (IAs) has not been well studied. We aimed to test the hypothesis of a positive association between hyperhomocysteinemia (HHcy) and IAs. METHODS: A case-control study was performed at a vascular neurosurgery unit in Brazil between 2016 and 2017. In total, 180 patients were included: 142 patients with previous IAs (case group) and 38 patients with a previous diagnosis of arteriovenous malformation and no aneurysms on imaging evaluation (control group). HHcy was defined as homocysteine levels greater than 15 µmol/L. Multivariate models were designed to adjust for potential confounders: age, sex, hypertension, dyslipidemia, and smoker status. RESULTS: The case group was older (56.3 ± 12.6 years vs. 40.9 ± 14.0 years, P < 0.001) and had a greater prevalence of women (76.1% vs. 55.3%, P = 0.012), as well as hypertension (45.1% vs. 2.6%, P < 0.001), dyslipidemia (60.6% vs. 10.5%, P = 0.001), and smokers (41.5% vs. 0.0%, P < 0.001). Median homocysteine in the cases was similar to the controls (10.5 µmol/L [8.3-14.0] vs. 10.7 µmol/L [8.2-13.3], respectively, P = 0.450). There was a trend toward greater HHcy prevalence in the case group (20.4% vs. 7.9%, P = 0.073). HHcy was associated with greater age, male sex, hypertension, and smoking status. After multivariate adjustment, HHcy had no association with IAs (odds ratio 1.34, 95% confidence interval 0.30-5.97, P = 0.703). CONCLUSIONS: No association was found between HHcy and IAs.

CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease.

We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [µ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [µ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [µ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

An MTHFR variant, plasma homocysteine levels and late-onset coronary artery disease in subjects from southern Iran.

There have been many controversial debates on the role of Hyperhomocysteinaemia (HHcy) as an independent risk factor for Coronary Artery Disease (CAD) during recent years. Furthermore, an alanine/valine (Ala/Val) gene polymorphism at 222nd amino acid of 5,10-methylenetetrahydrofolate reductase (MTHFR) has been considered as a factor that could render this enzyme thermolabile and less active which in turn may yield a subsequent increase in plasma total homocysteine (tHcy) levels. To assess whether this polymorphism is associated with increased risk of CAD and plasma levels of tHcy in a population from southern Iran, a total of 457 patients with angiographically documented multi-vessel CAD were compared with a control group comprised of 371 subjects with <30% stenosis in all major vessels. Nevertheless our results failed to admit a significant difference between CAD individuals and control subjects for Ala/Val polymorphism and plasma Hcy concentrations. However, plasma Hcy concentrations were significantly higher in individuals with Val/Val genotype than subjects with Ala/Ala genotype, but it didn't show a significant association with CAD in our population. Moreover, as the multiple linear regression analysis indicated, smoking habit, folate levels and the MTHFR Val/Val genotype were the only major predictors of tHcy concentrations in the current investigation.

Functional consequences of the collagen/elastin switch in vascular remodeling in hyperhomocysteinemic wild-type, eNOS-/-, and iNOS-/- mice.

A decrease in vascular elasticity and an increase in pulse wave velocity in hyperhomocysteinemic (HHcy) cystathionine-beta-synthase heterozygote knockout (CBS(-/+)) mice has been observed. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-tissue inhibitor of metalloproteinase (TIMP) inhibitory tertiary complex. However, the contribution of the nitric oxide synthase (NOS) isoforms eNOS and iNOS in the activation of latent MMP is unclear. We hypothesize that the differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP, resulting in vascular remodeling in response to HHcy. The overall goal is to elucidate the contribution of the NOS isoforms, endothelial and inducible, in the collagen/elastin switch. Experiments were performed on six groups of animals [wild-type (WT), eNOS(-/-), and iNOS(-/-) with and without homocysteine (Hcy) treatment (0.67 g/l) for 8-12 wk]. In vivo echograph was performed to assess aortic timed flow velocity for indirect compliance measurement. Histological determination of collagen and elastin with trichrome and van Gieson stains, respectively, was performed. In situ measurement of superoxide generation using dihydroethidium was used. Differential expression of eNOS, iNOS, nitrotyrosine, MMP-2 and -9, and elastin were measured by quantitative PCR and Western blot analyses. The 2% gelatin zymography was used to assess MMP activity. The increase in O(2)(-) and robust activity of MMP-9 in eNOS(-/-), WT+Hcy, and eNOS(-/-)+Hcy was accompanied by the gross disorganization and thickening of the ECM along with extensive collagen deposition and elastin degradation (collagen/elastin switch) resulting in a decrease in aortic timed flow velocity. Results show that an increase in iNOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance.

[Recurrent transient ischemic stroke in a young patient with papillary fibroelastoma of the mitral valve and hyperhomocysteinemia. A case report]. / Accidents vasculaires cérébraux ischémiques transitoires récurrents chez une jeune patiente secondaire à un fibroélastome papillaire de la valve mitrale et une hyperhomocystéïnémie. A propos d'une observation.

We describe a case of a young patient admitted for recurrent ischemic stroke caused by a papillary fibroelastoma of the mitral valve and a hyperhomocysteinemia. A papillary fibroelastoma is a benign cardiac tumor which can be associated with serious embolic complications. A moderate plasma level of hyperhomocysteinemia is considered as a risk factor of ischemic stroke. The authors suggest that this association increases the risk of ischemic stroke in their patient. The tumor was surgically removed to avoid new embolic events associated with a vitamin B supplementation. After surgery and acid folic supplementation, no recurrence was observed.

Mild hyperhomocysteinaemia is associated with increased aortic stiffness in general population.

Total homocysteine (tHcy) level was identified as a strong and independent predictor of cardiovascular events. We investigated the association between tHcy and mechanical properties of large arteries in a random, general population-based sample of 251 subjects (mean age 48 years). Large artery properties, such as aortic and peripheral (lower-limb) pulse wave velocity (PWV), and augmentation index of radial artery were measured using semi-automatic Sphygmocor device. Aortic PWV (APWV) positively correlated with tHcy (r = 0.28, P<0.0001), and a significant increasing trend of APWV was found by tHcy quartiles (P = 0.0003 by ANOVA). This association remained significant after adjustment for conventional cardiovascular risk factors (age, gender, smoking, overweight, hypertension, dyslipidaemia and impaired glucose metabolism) and for usual homocysteine confounders (folate, B12, renal function). Subjects with mild hyperhomocysteinaemia (i.e. with tHcy > or = 15 micromol/l) had 2.74 times higher risk of having their APWV over 8.42 m/s (i.e. in the top quartile). No such association was found either for PWV measured at lower extremity or for radial augmentation index. In conclusion, in our series of subjects from general population, we found a strong and independent relationship between homocysteine concentration and APWV, a parameter of stiffness of central arteries.

Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model.

BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by cystathionine beta-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis. METHODS: To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention. RESULTS: hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca2+/PO4(3-) and lower Ca2+/CO3(2-) molar ratios than in controls. Mineral crystallization was unchanged. CONCLUSION: In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We also conclude that the hCySH-supplemented chick is a promising model for study of the connective tissue abnormalities associated with homocystinuria and an important alternative model to the CBS knock-out mouse.

Homocysteine impairs coronary microvascular dilator function in humans.

OBJECTIVES: We sought to use positron emission tomography (PET) to test the hypothesis that hyperhomocysteinemia adversely effects coronary microvascular dilator function. BACKGROUND: Hyperhomocysteinemia is associated with abnormal endothelium-dependent vasodilation in peripheral human arteries. However, its effect on the coronary circulation is not known. METHODS: Eighteen healthy humans, age 24 to 56 years, were enrolled in a double-blind, crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) was determined by PET: after ingestion of placebo and after methionine-induced hyperhomocysteinemia. Further, brachial ultrasonography was used to assess flow-mediated vasodilation. Additionally, to assess the role of nitric oxide (NO) in adenosine-mediated vasodilation, the MBF response to adenosine was measured in the presence and absence of the NO synthase antagonist NG-monomethyl-l-arginine (l-NMMA) (0.3 mg/kg/min intravenously). RESULTS: Hyperhomocysteinemia resulted in a reduction in the MBF dose-response curve to adenosine (p < 0.05). This was most apparent with low dose adenosine, where MBF augmentation was significantly blunted during hyperhomocysteinemia (1.06 +/- 1.00 ml/min/g vs. 0.58 +/- 0.78 ml/min/g, placebo vs. methionine, p < 0.05). Similarly, flow-mediated brachial artery vasodilation was impaired during hyperhomocysteinemia (4.4 +/- 2.6% vs. 2.6 +/- 2.3%, placebo vs. methionine, p < 0.05). In a separate series of experiments, MBF during adenosine was reduced in the presence of l-NMMA (p < 0.05 analysis of variance). This was most apparent at the low dose of adenosine, where MBF response to adenosine was blunted in the presence of l-NMMA (2.08 +/- 1.34 ml/min/g vs. 1.48 +/- 1.32 ml/min/g, placebo vs. l-NMMA, p < 0.05). CONCLUSION: The data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability.

Severe atherosclerotic changes, including aortic occlusion, associated with hyperhomocysteinaemia and antiphospholipid antibodies.

Three patients are described with severe systemic atherosclerosis, including aortic occlusion, in the presence of a spectrum of risk factors, including hypercholesterolaemia, hypertension, a positive family history of cardiovascular problems, and hyperhomocysteinaemia. In all three patients high levels of anticardiolipin antibodies were found. The possible pathogenic role of antiphospholipid antibodies in atherosclerosis in the context of hyperhomocysteinaemia in these patients is discussed.