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BACKGROUND: Elevated plasma homocysteine is a risk factor for coronary artery disease (CAD) and thromboembolic disorders that seems also to be associated with chronic heart failure. OBJECTIVE: To evaluate the association between homocysteine and left ventricular dysfunction and to assess whether it is independent of CAD. PATIENTS AND METHODS: A prospective study evaluated this relationship in 709 patients referred for diagnostic coronary angiography, including 515 CAD and 194 patients without evidence of coronary artery lesions. RESULTS: The homocysteine level was significantly higher in the 187 patients with a left ventricular ejection fraction (LVEF) dysfunction < 40% (P < 0.0001) than in those without ventricular dysfunction. LVEF, NYHA functional class II or III and CAD, stable angina and hypertension were clinical characteristics that influenced total homocysteine level in univariate analysis. Homocysteine was significantly associated with LVEF and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in univariate regression (r = -0.267, 95% CI -0.33 to -0.19, P < 0.0001, and r = 0.381, 95% CI 0.28-0.47, P < 0.0001, respectively) and in multiple regression (P = 0.0022 and P = 0.0001, respectively). Other determinants were creatinine and vitamin B(12), but not folate. LVEF was a predictor of homocysteine > 15 micromol L(-1) in the whole population (P for trend < or = 0.0001) and in patients without documented CAD (P for trend = 0.0058). CONCLUSION: Our results showed an association of homocysteine with left ventricular systolic dysfunction and NT-pro-BNP that existed independently of documented CAD. Whether this association reflects a causative factor or a consequence of CHF and influences the prognosis of the disease remains an open question.

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Glomerular filtration is one of the major determinants of plasma total homocysteine (tHcy). To evaluate the respective roles of residual glomerular filtration (by measuring a specific protein marker, cystatin C), genetic polymorphisms and nutritional status in tHcy blood levels in end-stage renal disease patients (ESRD) under hemodialysis and supplemented with folate, we measured tHcy, folate, vitamin B12 (B12), creatinine, cystatin C, albumin and C-reactive protein and determined the polymorphism of methylenetetrahydrofolate reductase (MTHFR) (C677T and A1289C) and of methionine synthase (MS) (A2756G) in 114 ESRD patients before hemodialysis and 76 control subjects. All patients received a folate supplementation of 700 microg/day. Hyperhomocysteinemia was observed in all patients and exceeded the upper normal limit by 2-fold in 52.4% of the patients. Serum folate was significantly increased and the B12 level was not different from controls. Folate, Cystatin C and creatinine were significantly correlated to tHcy, while no correlation was found between tHcy, albumin and C-reactive protein. No difference in genotype frequency between ESRD patients and controls was found for MTHFR A1289C and MS A2756G. The MTHFR 677TT genotype was less frequent and was associated with a significantly higher tHcy level in patients. Folate and residual glomerular filtration estimated by cystatin C and creatinine levels were two independent determinants of tHcy in ESRD patients. These data suggest that hyperhomocysteinemia is a consequence as well as a complicating factor of renal failure.

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The importance of accurate methods for homocysteine measurement has been emphasized. We compared the results obtained with the most commonly used high-performance liquid chromatography (HPLC) assay, and two recently commercially available methods: another HPLC and a fluorescence polarization immunoassay, in plasmas from normo- or hyperhomocysteinemic patients. A significant agreement between the different methods in classifying the results as hyper or normal-homocysteinemia was observed. However, a significant difference between the results was found. Standardization is urgently necessary to improve the concordance of homocysteine determination.

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Transcobalamin (TC) is the plasma transporter that delivers vitamin B(12) to cells. We have already reported that HT-29 and Caco-2 cells secrete different TC variants. HT-29 secretes 2 TC isoproteins (codon 259-Pro/Arg [259-P/R]), exhibiting unequal concentrations (TC 259-P > TC 259-R), and Caco-2 cells only secrete the phenotype 259-R. We investigated the relation between phenotypic and genetic TC polymorphism in HT-29 cells transfected with Caco-2 TC complementary DNA and in 159 healthy Caucasians. We found that codon 259-R is buried and, thus, the genetic polymorphism provides no explanation why the TCs from HT-29 and Caco-2 cells have different isoelectric points in nondenaturing isoelectric focusing (IEF). The newly translated TC in HT-29 cells from the Caco-2 complementary DNA recombinant plasmid had the same isoelectric point as the TC constitutively expressed in HT-29 cells, suggesting that TC phenotypic variability involves a specific cell folding of the protein. The codon 259 polymorphism was found to have a biallelic distribution: homozygotes P = 34.6%, heterozygotes R/P = 47.8%, and homozygotes R = 17.6%. In heterozygous samples, the IEF showed that the TC 259-P/TC 259-R ratio = 1.6. The blood apo-TC concentration of 259-P homozygous Caucasians was significantly higher than that of homozygous 259-R (P <.0001) and heterozygous (P <.0006) Caucasians. The heterozygotes 259-R/P had homocysteine concentration significantly higher than the homozygotes 259-R and 259-P (P =.02 and P =.01, respectively). In conclusion, TC codon-259 polymorphism affects TC plasma concentration and may interfere in vitamin B(12) cellular availability and homocysteine metabolism.

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Homocysteine and vitamins B were correlated with coronary artery disease in patients undergoing diagnostic coronary angiography. 160 patients having > or =1 stenosis (G1), 55 patients having normal coronary arteries (G2) and 171 healthy volunteers (G3) were prospectively recruited. Homocysteine levels were significantly higher in patients, particularly in those with normal coronary angiograms, than in healthy subjects (13.8 +/-6.3 micromol/L in G1 (p < 0.0001) and 15.2 +/- 8.8 micromol/L in G2 (p < 0.0001) versus 10.1 +/- 3.1 micromol/L in G3). Homocysteine levels were not related to the extent of coronary artery disease. In patients with normal angiogram, vitamin B12 and folate levels were significantly higher compared with the other groups (p < 0.05 and p < 0.001, respectively) showing that vitamin B deficiency was not involved in the hyperhomocysteinemia. In conclusion, homocysteine and vitamins B levels do not contribute to discriminate for the presence of coronary artery disease in patients undergoing diagnostic coronary angiography. Homocysteine levels, however, were higher in patients referred for coronary angiography than in healthy controls.

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BACKGROUND: Inflammation might promote the development of atherosclerosis, and high levels of C-reactive protein (CRP) and fibrinogen are associated with an increased risk of acute coronary events. OBJECTIVE: We assessed the levels of CRP and other risk factors in patients with angiographically documented coronary artery disease compared with healthy volunteers and patients undergoing coronary angiography who had normal coronary angiograms. METHODS: Ultrasensitive immunoassay was used to measure CRP levels in 142 patients with coronary disease (group 1), 37 patients with normal coronary angiograms (group 2), and 37 control healthy subjects (group 3). RESULTS: CRP levels were higher in group 1 (7.1 +/- 11.2 mg/L) compared with group 2 (4.8 +/- 4.0 mg/L) and group 3 (2.3 +/- 3.6 mg/L). In group 1, CRP levels were higher for patients with previous myocardial infarction (8.7 +/- 9.2 mg/L) or unstable angina (11.6 +/- 18.8 mg/L). Though CRP levels in patients with coronary artery disease and stable symptoms were higher compared with healthy volunteers (5.15 +/- 7.2 mg/L vs 2.3 +/- 3.6 mg/L, P <.05), they were similar to those observed in the control population of patients with normal coronary angiograms (4.8 +/- 4.0 mg/L). Furthermore, CRP levels were positively correlated to plasma fibrinogen but not to Chlamydia pneumoniae or Helicobacter pylori serology. CONCLUSION: These results suggest that CRP has a strong association with acute coronary events but do not support the hypothesis that CRP is a potent determinant of chronic stable coronary disease.

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