Hyperhomocysteinemia is Associated with Aortic Atheroma Progression in Stroke/TIA Patients

Department of Neurology, University of South Carolina School of Medicine Columbia, SC, USA.
Frontiers in Neurology 11/2010; 1:131. DOI: 10.3389/fneur.2010.00131
Source: PubMed


Significance: Aortic arch (AA) atheroma and AA atheroma progression are independent risk factors for recurrent vascular events in stroke/transient ischemic attack (TIA) patients. Total homocysteine level (tHcy) is an independent risk marker for atherosclerosis including that found in AA. The purpose of this study was to prospectively test the association between AA atheroma progression and tHcy. Methods: This is a cohort study of 307 consecutive hospitalized stroke/TIA patients undergoing transesophageal echocardiogram (TEE) as a part of their clinical workup. Measurable AA atheroma was detected in 167 patients of whom 125 consented to a protocol-mandated follow-up TEE at 12 months. Patients had evaluation for vascular risk factors, dietary factors (folate, B12 and pyridoxine), and methylene tetrahydrofolate reductase (MTHFR) polymorphism. One hundred eighteen stroke/TIA patients had tHcy, acceptable paired AA images, and detailed plaque measurements. An increase by ≥1 grade of AA atheroma was defined as progression. Results: Of the 118 patients, 33 (28%) showed progression and 17 (14%) showed regression of their index arch lesion at 1 year. tHcy (≥14.0 μmol/l) was significantly associated with progression on both univariate (RR = 3.4, 95% CI 2.0-5.8) and multivariate analyses (adjusted RR = 3.6, 95% CI 2.2-4.6). The changes in AA plaque thickness (r(2) = 0.11; p < 0.001) and AA plaque area (r(2) = 0.08; p = 0.002) correlated with tHcy. tHcy was associated with change in plaque thickness over 12 months, independent of age, dietary factors, renal function and MTHFR polymorphism (Standardized β-coefficient 0.335, p = 0.02). Conclusions: Our results validate the association and a linear correlation between tHcy and progression of AA atheroma.

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Available from: Leema Reddy Peddareddygari, Jan 16, 2015
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    • "One major consequence of MD deficiency is a mild or moderate HHcy characterized by circulating total Hcy concentrations in the 15–30 or 31–100 μM range, respectively. This condition has long been associated with an elevated risk of chronic pathologies like atherosclerosis , ischemic heart disease and stroke in humans [5]. MD deficiency and subsequent HHcy can occur in individuals with increased requirement and/or inadequate intake of either MD, e.g. during pregnancy or aging [6]. "
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    ABSTRACT: Methyl donor (MD: folate, vitamin B12 and choline) deficiency causes hyperhomocysteinemia, a risk factor for cardiovascular diseases. However, the mechanisms of the association between MD deficiency, hyperhomocysteinemia, and cardiomyopathy remain unclear. Therefore, we performed a proteomic analysis of myocardium of pups from rat dams fed a MD-depleted diet to understand the impact of MD deficiency on heart at the protein level. Two-dimension gel electrophoresis and mass spectrometry-based analyses allowed us to identify 39 proteins with significantly altered abundance in MD-deficient myocardium. Ingenuity Pathway Analysis showed that 87% of them fitted to a single protein network associated with developmental disorder, cellular compromise and lipid metabolism. Concurrently increased protein carbonylation, the major oxidative post-translational protein modification, could contribute to the decreased abundance of many myocardial proteins after MD deficiency. To decipher the effect of MD deficiency on the abundance of specific proteins identified in vivo, we developed an in vitro model using the cardiomyoblast cell line H9c2. After a 4-day exposure to a MD-deprived (vs. complete) medium, cells were deficient of folate and vitamin B12, and released abnormal amounts of homocysteine. Western blot analyses of pup myocardium and H9c2 cells yielded similar findings for several proteins. Of specific interest is the result showing increased and decreased abundances of prohibitin and α-crystallin B, respectively, which underlines mitochondrial injury and endoplasmic reticulum stress within MD deficiency. The in vitro findings validate the MD-deficient H9c2 cells as a relevant model for studying mechanisms of the early metabolic changes occurring in cardiac cells after MD deprivation.
    The Journal of nutritional biochemistry 01/2013; 24(7). DOI:10.1016/j.jnutbio.2012.09.008 · 3.79 Impact Factor
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    ABSTRACT: Methylenetetrahydrofolate reductase (MTHFR) enzyme is one of the most important enzymes with a pivotal role in the folate metabolism and DNA synthesis pathways. Single nucleotide polymorphism (SNPs) in the coding gene has been related to many medical diseases as well as diverse malignancies including the prostate cancer which is the leading cause of the cancer deaths in men and one of the major public health problems. The goal of this study is to determine the relationship between the MTHFR C677T SNP and the prostate adenocarcinoma in Iranian males attending to the Labbafi-nezhad hospital in Tehran. In this Case-control unmatched study, 67 and 75 paraffinized tissue samples were taken out of the specimens diagnosed previously as the prostatic adenocarcinoma and nodular prostatic hyperplasia for the case and control groups respectively. MTHFR C677T genotyping was done by the use of multiplex ARMS-PCR and frequencies of the alleles were compared between the case and control groups as well as calculating the deviation from Hardy-Weinberg equilibrium and Odds Ratio for the "T" allele regarding the prostatic carcinoma. The observed rates in the control group were not too different from that of expected from Hardy-Weinberg equilibrium (P=0.407). Frequencies of the possible genotypes were as follows: CC, 43.28% vs. 42.67%; CT, 49.25% vs. 52% and CT, 7.46% vs. 5.33% in the case and control groups respectively (P=0.85). 1.37 times increased risk was found for the homozygote carriers of C677T variant (OR: 1.37, 95% CI: 0.33-5.6; P=0.653) which is however statistically not significant. No association has been evident between the MTHFR 677C>T polymorphism and the risk of prostatic carcinoma in this study confirming the findings of some of the previous attempts; however, (OR: 1.37, 95% CI: 0.33-5.6) implies a slight effect of the homozygote on the carcinogenesis. Thus larger studies especially with a greater number of the smaples are recommended.
    Acta medica Iranica 10/2012; 50(10):657-63.
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    ABSTRACT: Purpose: To assess the outcome of patients with medically treated hyperhomocysteinemia (HHC) requiring intervention for critical limb ischemia (CLI). Methods: A parallel observational study was conducted to compare the clinical and revascularization outcomes of CLI patients who received standardized treatment for HHC preoperatively (folic acid and vitamin B12) vs. contemporaneous patients with normal homocysteine levels. The threshold for HHC diagnosis was 13.0 μmol/L. From 2009 to 2011, 169 patients underwent revascularization procedures for CLI. Of these, all 66 patients (40 men; mean age 69.6 ± 11.2 years) with HHC (mean 17.3 μmol/L, range 13.5-34.9) were treated to normalize the homocysteine level prior to lower limb revascularization. The remaining 103 patients (58 men; mean age 72.7±8.1 years) had normal homocysteine levels (8.2 μmol/L, range 5-12.3) before revascularization. The primary endpoint was symptomatic and hemodynamic improvement in the treated HHC group. The secondary endpoints were all-cause survival, binary restenosis, reintervention, amputation-free survival, and major adverse events. The treated HHC cohort was compared to an age/sex-matched historical group of patients with untreated HHC from 2002 to 2006 before HHC pretreatment became routine. All interventions (endovascular, hybrid, and open) were performed by the same surgeon, and the groups were evenly matched. Results: Patients with HHC were treated for a mean 12.2 days, which significantly reduced their mean homocysteine level after 3 weeks to 10.1 μmol/L (range 6.2-14.4, p<0.05). After revascularization, immediate clinical improvement was similar between normal homocysteine and medically corrected HHC groups. There was no significant difference in time to binary restenosis (p=0.822). Secondary endpoints and all-cause mortality were similar. Multivariate logistic regression showed that untreated HHC was a significant factor for graft occlusion and limb loss (p<0.0001), but medically corrected HHC was no longer predictive of adverse operative outcome. Conclusion: Patients with medically corrected HHC have similar outcomes compared to those with normal homocysteine levels. Thus, aggressively treating HHC with folic acid and vitamin B12 may help enhance the clinical outcome of CLI patients undergoing revascularization.
    Journal of Endovascular Therapy 12/2012; 19(6):815-25. DOI:10.1583/JEVT-12-3949MR.1 · 3.35 Impact Factor
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