title: Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic patients.
abstract: BACKGROUND
  Elevated low density lipoproteins (LDL)-cholesterol and homocysteine levels have both been found to be associated with an increased risk for atherosclerotic vascular disease. To assess the effects of elevated homocysteine levels in hypercholesterolemic subjects on endothelial function, we examined basal and stimulated nitric oxide (NO) mediated vasodilation in the forearm vascular bed in hypercholesterolemic subjects with normal or elevated homocysteine levels.
  
  
  METHODS
  Twenty-seven white subjects (age: 48 +/- 12 years) with elevated LDL-cholesterol (> or = 160 mg/dl) were divided into two groups with normal (n = 11) or mildly elevated (n = 16) homocysteine plasma concentration. We used strain gauge plethysmography to measure changes in forearm blood flow in response to intraarterial administration of increasing doses of acetylcholine (3, 12, 24, 48 microg/min), sodium nitroprusside (200, 800, 3200 ng/min), and N-monomethyl L-arginine (L-NMMA) (1, 2, 4 micromol/min). Total homocysteine plasma concentrations were determined by high performance liquid chromatography fluorimetry.
  
  
  RESULTS
  Endothelium independent vascular relaxation tested by i.a. sodium nitroprusside and changes in forearm blood flow after i.a. L-NMMA indicating basal production and release of nitric oxide were similar between the two groups with normal or elevated homocysteine levels. In contrast, endothelium dependent vasodilation as assessed by the administration of i.a. acetylcholine differed between the groups with normal or elevated homocysteine levels for all doses tested (MANOVA P < 0.01: ACH 48 microg/min: 480 +/- 237% with normal vs 234 +/- 130% with elevated homocysteine; P < 0.002). This was significant even after taking possible covariates such as age, blood pressure, body mass index, LDL-, high density lipoproteins (HDL)-cholesterol, and trigylcerides into account (MANOVA P < 0.02).
  
  
  CONCLUSIONS
  From our study we conclude that homocysteine impairs endothelium dependent vasodilation in subjects with elevated LDL-cholesterol levels. The most intriguing finding is that even mildly elevated homocysteine levels seem to be of crucial importance for deterioration of endothelial function, especially if other cardiovascular risk factors such as hypercholesterolemia preexist.
authors.affiliation: Department of Medicine IV/Nephrology, University of Erlangen-Nürnberg, Nurnberg, Germany.
authors.forename: M P
authors.initials: MP
authors.lastname: Schlaich
authors.forename: S
authors.initials: S
authors.lastname: John
authors.forename: J
authors.initials: J
authors.lastname: Jacobi
authors.forename: K J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: R E
authors.initials: RE
authors.lastname: Schmieder
mesh_terms: D000328:Adult; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D014664:Vasodilation
chemical_list: D006710:Homocysteine; D009569:Nitric Oxide