Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease

OBJECTIVE: Prostaglandin E1 (PGE-1) is a potent vasodilative agent which has been used to bridge patients with chronic heart failure listed for heart transplantation (HTX). In various experimental settings PGE-1 appears to stimulate angiogenesis by inducing vascular endothelial growth factor expression. This observational clinical study sought to investigate the angiogenic effects of PGE-1 in the failing human heart. METHODS: Neovascularization was investigated in 14 explanted hearts from patients with ischemic cardiomyopathy (ICMP) who had been bridged to HTX with PGE-1 (8+/-1 mg/kg/min, 97+/-75.6 days) and compared with 14 hearts who did not receive PGE-1 prior to HTX. In three sectional areas obtained from the left ventricular wall CD34, von Willebrand factor (vWf), nuclear Ki67 (MIB-1), and VEGF were quantified by immunohistochemistry to estimate capillary density and endothelial cell proliferation. Additionally, to investigate a possible angiogenic effect of PGE-1 in vitro, cultured human coronary artery smooth muscle cells (HCASMCs) were treated with PGE-1. RESULTS: PGE-1-treated patients had significantly more CD34- and vWf-positive cells in the subepicardium (both P<0.01), myocardium (both P<0.0001) and subendocardium (P<0.01 and P<0.001) as compared to the nonPGE-1 group. Proliferative endothelial activity expressed by the presence of MIB-1- and VEGF-positive cells (both P<0.0001 in all layers) was increased more than twofold. Addition of PGE-1 to HCASMCs in cell culture resulted in a significant increase in VEGF production (164.0+/-19.7 pg/10(5) cells/24 h, P<0.005) as compared to the control cell line (66.6+/-8.7 pg/10(5) cells/24 h, P<0.005). CONCLUSIONS: Our data demonstrate that PGE-1 is a potent stimulator of angiogenesis via upregulation of VEGF expression. The induction of therapeutic angiogenesis in patients with severe ICMP might explain the favorable clinical outcome in PGE-1 treated patients until HTX.