Electronegative low-density lipoprotein increases the risk of ischemic lower-extremity peripheral artery disease in uremia patients on maintenance hemodialysis.

Electronegative low-density lipoprotein (LDL) has been shown to increase coronary artery disease risk in hemodialysis patients, but its effect on the risk of peripheral artery disease (PAD) remains unclear. We separated plasma LDL from 90 uremia patients undergoing hemodialysis into 5 subfractions (L1-L5) according to charge by using fast-protein liquid chromatography with an anion-exchange column and examined the distribution of L5-the most electronegative LDL subfraction-in total LDL (i.e. L5%). During a 5-year period, we followed up with these patients until the occurrence of ischemic lower-extremity PAD. During the follow-up period, ischemic lower-extremity PAD developed in 24.4% of hemodialysis patients. L5% was higher in hemodialysis patients in whom ischemic lower-extremity PAD occurred (3.03% [IQR, 2.36-4.54], n = 22) than in hemodialysis patients in whom PAD did not occur (1.13% [IQR, 0.90-1.83], n = 68) (p < 0.001). Furthermore, L5% significantly increased the adjusted hazard ratio of ischemic lower-extremity PAD (1.54 [95% CI, 1.14-2.10]) (p = 0.005). Flow-mediated dilation was negatively associated with L5% (p < 0.001). Additionally, in vivo experiments from mice showed that L5 compromised endothelium-dependent vascular relaxation through a nitric oxide-related mechanism. Our findings indicate that increased L5% may be associated with the occurrence of ischemic lower-extremity PAD in hemodialysis patients.

Electronegative Low-density Lipoprotein Increases Coronary Artery Disease Risk in Uremia Patients on Maintenance Hemodialysis.

Electronegative low-density lipoprotein (LDL) is a recognized factor in the pathogenesis of coronary artery disease (CAD) in the general population, but its role in the development of CAD in uremia patients is unknown. L5 is the most electronegative subfraction of LDL isolated from human plasma. In this study, we examined the distribution of L5 (L5%) and its association with CAD risk in uremia patients.The LDL of 39 uremia patients on maintenance hemodialysis and 21 healthy controls was separated into 5 subfractions, L1-L5, with increasing electronegativity. We compared the distribution and composition of plasma L5 between uremia patients and controls, examined the association between plasma L5% and CAD risk in uremia patients, and studied the effects of L5 from uremia patients on endothelial function.Compared to controls, uremia patients had significantly increased L5% (P < 0.001) and L5 that was rich in apolipoprotein C3 and triglycerides. L5% was significantly higher in uremia patients with CAD (n = 10) than in those without CAD (n = 29) (P < 0.05). Independent of other major CAD risk factors, the adjusted odds ratio for CAD was 1.88 per percent increase in plasma L5% (95% CI, 1.01-3.53), with a near-linear dose-response relationship. Compared with controls, uremia patients had decreased flow-mediated vascular dilatation. In ex vivo studies with preconstricted rat thoracic aortic rings, L5 from uremia patients inhibited acetylcholine-induced relaxation. In cultured human endothelial cells, L5 inhibited endothelial nitric oxide synthase activation and induced endothelial dysfunction.Our findings suggest that elevated plasma L5% may induce endothelial dysfunction and play an important role in the increased risk of CAD in uremia patients.