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Does lipoprotein(a) impair endothelial function?
M P Schlaich1, S John, M R Langenfeld
1Department of Medicine IV/Nephrology, University of Erlangen-Nuremberg, Nuremberg, Germany.
Insights
High lipoprotein(a) [Lp(a)] levels may increase nitric oxide (NO) production as a compensatory response in the endothelium. This suggests a potential mechanism for Lp(a)-associated cardiovascular risk.
Area of Science:
- Cardiovascular Science
- Endocrinology
- Vascular Biology
Background:
- Elevated lipoprotein(a) [Lp(a)] is linked to increased coronary heart disease risk.
- Endothelial dysfunction is an early marker of atherosclerosis.
- The impact of Lp(a) on nitric oxide (NO)-mediated vasodilation is not fully understood.
Purpose of the Study:
- To investigate the hypothesis that lipoprotein(a) impairs endothelial function.
- To determine the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm.
Main Methods:
- Strain gauge plethysmography used to measure forearm blood flow.
- Intraarterial infusions of acetylcholine, sodium nitroprusside, and N-monomethyl L-arginine (L-NMMA) administered.
- Lp(a) plasma concentrations measured via rocket immunoelectrophoresis in 57 subjects.
Main Results:
- No correlation found between Lp(a) levels and endothelium-dependent vasodilation (acetylcholine) or endothelium-independent relaxation (sodium nitroprusside).
- Forearm blood flow responses to L-NMMA, indicating basal NO production, differed significantly across Lp(a) tertiles.
- Higher Lp(a) levels correlated with a greater vasoconstrictive response to L-NMMA, suggesting increased basal NO release.
Conclusions:
- Enhanced vasoconstriction to L-NMMA in subjects with high Lp(a) suggests increased basal NO production.
- This response may represent a compensatory endothelial mechanism against unknown Lp(a)-induced atherosclerotic effects.
- Lp(a) is an independent determinant of forearm blood flow response to L-NMMA.
Objectives:
This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function.
Background:
Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed.
Methods:
Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 microg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl L-arginine (L-NMMA) (1, 2 and 4 micromol/min) in 57 white subjects (mean age +/- SD 37 +/- 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis.
Results:
Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial L-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 +/- 20.3 mg/dl) had a much greater vasoconstrictive response to L-NMMA than patients in the lowest Lp(a) tertile (4.8 +/- 2.5 mg/dl): 2 micromol/min of L-NMMA, -23.6 +/- 22.5% vs. -10.4 +/- 9.1% (p < 0.02); 4 micromol/min of L-NMMA, -27.8 +/- 10.3% vs. -17.6 +/- 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 micromol/min of intraarterial L-NMMA (r = -0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to L-NMMA (p < 0.02).
Conclusions:
The endothelium-dependent vasoconstrictive response to L-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.