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Mildly elevated homocysteine concentrations impair endothelium dependent vasodilation in hypercholesterolemic
M P Schlaich1, S John, J Jacobi
1Department of Medicine IV/Nephrology, University of Erlangen-Nürnberg, Nurnberg, Germany.
Insights
Elevated homocysteine impairs blood vessel function in individuals with high LDL-cholesterol. Even mildly increased homocysteine levels significantly worsen endothelial function, especially when combined with hypercholesterolemia.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Metabolic Disease
Background:
- Elevated low-density lipoprotein (LDL)-cholesterol and homocysteine are linked to atherosclerotic vascular disease risk.
- Endothelial dysfunction is a key factor in the development of atherosclerosis.
Purpose of the Study:
- To investigate the impact of elevated homocysteine on endothelial function in hypercholesterolemic individuals.
- To assess nitric oxide (NO)-mediated vasodilation in response to varying homocysteine levels.
Main Methods:
- Twenty-seven hypercholesterolemic subjects were divided into normal and elevated homocysteine groups.
- Strain gauge plethysmography measured forearm blood flow changes.
- Intraarterial administration of acetylcholine, sodium nitroprusside, and L-NMMA assessed vasodilation and NO production.
Main Results:
- Endothelium-independent vasodilation and basal nitric oxide production were similar between groups.
- Endothelium-dependent vasodilation via acetylcholine was significantly impaired in the elevated homocysteine group (MANOVA P < 0.01).
- This impairment remained significant after adjusting for covariates like age, blood pressure, and lipid profiles.
Conclusions:
- Homocysteine significantly impairs endothelium-dependent vasodilation in hypercholesterolemic subjects.
- Even mildly elevated homocysteine levels are critical for endothelial dysfunction, particularly with pre-existing hypercholesterolemia.
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.