Placental growth factor 2 — A potential therapeutic strategy for chronic myocardial ischemia

Objectives We investigated whether sustained infusion of recombinant human placental growth factor-2 (rhPlGF-2) improves myocardial perfusion and left ventricular (LV) function in a porcine model of ischemic cardiomyopathy (ICM). Methods We induced myocardial ischemia using a flow-limiting stent in the LAD. Four weeks later, we randomized pigs with confirmed myocardial dysfunction to blinded rhPlGF-2 administration (PlGF2, 15μg/kg/day, 14days) or PBS (CON). At 8weeks, we measured hemodynamics, contractile function and regional perfusion at rest and during stress using MRI and microspheres. We evaluated neovascularization post mortem. Results RhPlGF-2 administration increased PlGF serum levels more than 63-fold (833±361 versus 11±5pg/ml CON, P<0.05) without adverse effects. After 4weeks, rhPlGF-2 significantly enhanced perfusion in the ischemic region at rest (0.83±0.32 versus 0.58±0.21ml/min/g CON, P<0.05) and during hyperemia (1.50±0.50 versus 1.02±0.46ml/min/g CON, P<0.05). Consequently, regional contractile function in rhPlGF-2-treated pigs improved at rest (37±15% versus 23±9% CON, P<0.05) and during high dose dobutamine stress (53±31% versus 27±16% CON, P<0.05). Enhanced perfusion translated into a greater improvement in LV ejection fraction and in preload-recruitable stroke work in rhPlGF-2-treated animals than in CON (52±11 versus 41±9%, and 76±24 versus 41±21mmHg, respectively, P<0.05 for both), which was associated with significantly greater vascular density in the ischemic region. Conclusions In chronic ICM, systemic rhPlGF-2 administration significantly enhances regional myocardial perfusion, contractile function at rest and during stress, and induces a prominent recovery of global cardiac function. PlGF-2 protein infusion is safe and may represent a promising therapy in chronic ICM.