Abstract 1463: Serum Levels of Circulating Soluble VEGF- Receptor 1 (sFLT-1) Modulate PlGF-Induced Impairment of Systemic Vasoreactivity in Patients With Coronary Artery Disease
Background: Placental Growth Factor (PlGF), a member of the VEGF family, acts as a proximal upstream mediator of vascular inflammation and was shown to be a powerful predictor for impaired short- and long- term prognosis after ACS. Since the proinflammatory effects of PlGF can be specifically inhibited by soluble Fms-like tyrosine kinase- 1 (sFLT-1), we tested the hypothesis that circulating levels of endogenous sFLT-1 modulate the detrimental effects of PlGF on systemic vasoreactivity in patients (pts) with CAD.
Methods and Results: Vasoreac-tivity was assessed in 100 male pts with documented CAD by measuring endothelium-dependent (acetylcholine (ACH) 10–50 μg/min) and endothelium- independent (sodium-nitroprusside (SNP) 2– 8 μg/min) forearm blood flow responses (FBF) using venous occlusion plethysmography. There was an inverse correlation between PlGF serum levels and ACH-induced FBF response (r=−0.21, p<0.05). Pts with elevated PlGF levels (≥median) had significantly impaired FBF responses to ACH compared to pts with PlGF < median (max. ACH induced FBF 12.4 vs. 16.4 ml*min−1*100 ml forearm−1, p<0.01). There was no correlation between serum levels of PlGF and its circulating soluble receptor, sFLT-1. Elevated sFLT-1 serum levels completely abrogated the impairment of ACH- induced FBF responses in pts with elevated PlGF levels. In contrast, sFLT-1 levels did not modulate the association between VEGF serum levels and ACH- induced FBF. On multivariable analysis including classical risk factors for CAD and concurrent medication, only PlGF and sFLT-1 serum levels remained as significant independent predictors for the ACH- induced FBF response.
Conclusion: In pts with CAD, increased systemic levels of PlGF are associated with profoundly impaired systemic endothelial vasoreactivity. Elevated levels of its circulating soluble receptor, sFLT-1 selectively abrogate the detrimental effect of PlGF on endothelial vasoreactivity supporting the hypothesis that sFLT-1 binds to and inactivates PlGF and, hereby counteracts endothelial activation caused by PlGF- mediated vascular inflammatory processes. Therapeutic interventions aiming to increase circulating sFLT-1 levels may represent a promising strategy to improve outcome in pts with CAD.