Vascular endothelial growth factor, left ventricular dysfunction and mortality in hemodialysis patients.

ABSTRACT

OBJECTIVES: Vascular endothelial growth factor induces nitric oxide-dependent angiogenic effects and participates in the inflammatory response. This cytokine is over-expressed in the myocardium in experimental models of pressure overload and renal mass ablation, and vascular endothelial growth factor is increased in end-stage renal disease. We investigated the relationship between vascular endothelial growth factor, left ventricular function (by midwall fractional shortening) and mortality in a prospective cohort study in 228 hemodialysis patients. RESULTS: Serum vascular endothelial growth factor concentration was associated directly with interleukin-6 and tumor necrosis factor-alpha (P < 0.01) and inversely with albumin (P = 0.007) but was independent of the endogenous inhibitor of nitric oxide synthesis, asymmetric dimethylarginine. Vascular endothelial growth factor was inversely related with midwall fractional shortening (P = 0.002) and predicted mortality (P = 0.02). In multivariate analyses testing the involvement of this angiogenic cytokine in left ventricular dysfunction and death, these links remained substantially unmodified after adjustment for Framingham risk factors, risk factors peculiar to end-stage renal disease (Hb, Ca, P) and previous cardiovascular complications. However, these links became weaker and not significant when biomarkers of inflammation and asymmetric dimethylarginine were sequentially introduced into the multivariate models. In crude and adjusted analyses, left ventricular function was lowest in patients who displayed both high vascular endothelial growth factor and high asymmetric dimethylarginine, intermediate in patients with either high vascular endothelial growth factor or high asymmetric dimethylarginine and highest in those with low asymmetric dimethylarginine and low vascular endothelial growth factor (P = 0.001). CONCLUSION: Vascular endothelial growth factor is associated with left ventricular systolic dysfunction and mortality in hemodialysis patients. Vascular endothelial growth factor appears to be in the pathway whereby inflammation and nitric oxide inhibition lead to cardiomyopathy and death in hemodialysis patients.