sFlt-1, a Potential Antagonist for Exogenous VEGF To the Editor: Results from the VEGF in Ischemia for Vascular Angiogen-

Exogenous VEGF To the Editor: Results from the VEGF in Ischemia for Vascular Angiogenesis (VIVA) clinical trial, which demonstrated the therapeutic use of vascular endothelial growth factor (VEGF) in angina, were presented at the 48th Scientific Sessions of the American College of Cardiology.1 These results indicated that no significant difference existed in the symptoms or clinical events of patients infused with VEGF and those of the placebo group. Although this may be due in part to inadequate dosage or an inappropriate delivery method, this unexpected result could also be attributed to the presence of the soluble VEGF receptor Flt-1 (sFlt-1). An analysis of this receptor reveals that it, like the membrane-bound receptor, binds VEGF with high affinity and inhibits VEGFmediated events in vitro.2,3 Our laboratory developed a specific and sensitive enzymelinked immunosorbent assay using commercial antibodies and recombinant standards (R&D Systems) to measure the plasma levels of free sFlt-1, which can bind VEGF, in vitro. This assay was developed for an ongoing study testing the hypothesis that patients with atherosclerotic vascular disease will have abnormal levels of VEGF and sFlt-1 when compared with healthy controls. Our pilot study of 60 patients (45 men; mean age, 58610 years) with coronary artery disease (all with a previous myocardial infarction; samples collected 6 weeks post–myocardial infarction) were compared with an equal number of ageand sexmatched healthy controls. The median level of VEGF (as determined by ELISA, R&D Systems) in the citrated plasma from patients was 430 pg/mL (interquartile range, 136 to 1004 pg/mL); the median sFlt-1 level was 14 ng/mL (range, 1 to 45 ng/mL). In the controls, the median levels of VEGF and sFlt-1 were 75 pg/mL (interquartile range, 20 to 125 pg/mL) and 23 ng/mL (range, 15–37 ng/mL), respectively. An analysis of the data using the Mann-Whitney U test confirmed that VEGF levels in patients with coronary artery disease were significantly higher than those of the control group (P,0.001) but that levels of sFlt-1 were lower in patients compared with controls (P,0.05). Nevertheless, levels of sFlt-1 in both patients and controls were 33-fold and 306-fold greater than those of VEGF, respectively. Although early clinical trials and studies of animal models indicated that the therapeutic use of VEGF could improve collateral circulation,4,5 the high plasma levels of sFlt-1 may act as a potential antagonist for VEGF. Thus, any exogenously administrated VEGF would have to completely neutralize its soluble receptor (sFlt-1) before adequate levels would reach target organ(s). This may have contributed to the lack of effect of VEGF that was experienced by the VIVA investigators.