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

ObjectivesWe 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).MethodsWe 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, 15 μg/kg/day, 14 days) or PBS (CON). At 8 weeks, we measured hemodynamics, contractile function and regional perfusion at rest and during stress using MRI and microspheres. We evaluated neovascularization post mortem.ResultsRhPlGF-2 administration increased PlGF serum levels more than 63-fold (833 ± 361 versus 11 ± 5 pg/ml CON, P < 0.05) without adverse effects. After 4 weeks, rhPlGF-2 significantly enhanced perfusion in the ischemic region at rest (0.83 ± 0.32 versus 0.58 ± 0.21 ml/min/g CON, P < 0.05) and during hyperemia (1.50 ± 0.50 versus 1.02 ± 0.46 ml/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 ± 21 mmHg, respectively, P < 0.05 for both), which was associated with significantly greater vascular density in the ischemic region.ConclusionsIn 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.