Percutaneous transluminal coronary angioplasty or stenting and coronary artery bypass surgery are effective therapies for relief of angina caused by coronary artery disease (CAD). However many patients with CAD have failed attempts at conventional revascularization or remain symptomatic despite optimized anti-ischemic medical therapy. For this growing number of patients, there is a need for novel therapeutic approaches. Experimental studies in animal models indicate that primitive pluripotential cells (or ?stem? cells) from bone marrow may localize to ischemic myocardium, differentiate along endothelial, smooth muscle, and cardiomyocyte lineages, and improve cardiac performance. A recent report has suggested that granulocyte-macrophage colony stimulating factor, which mobilizes stem cells from bone marrow into the circulation, may improve collateral blood flow to ischemic myocardium in patients with CAD. The purpose of this protocol is to test the effectiveness of a related cytokine, granulocyte colony stimulating factor (G-CSF), that more potently mobilizes stem cells from bone marrow, for the relief of myocardial ischemia and improvement in myocardial contractility during stress in patients with CAD who are not good candidates for conventional revascularization, or who do not want further attempts at conventional revascularization, and who remain symptomatic on medical therapy. Our hypothesis is that G-CSF will improve blood flow to the myocardium and the left ventricular contractile response to stress by mobilizing pluripotential cells from bone marrow with localization to ischemic regions of the heart, resulting in development of new arteries and regeneration of contractile cardiomyocytes. The primary end-point of the Phase I (safety) component of this study is absence of cardiovascular adverse events associated with increased white blood cell counts following G-CSF administration in patients with CAD. The secondary end-point for Phase I is determination of platelet aggregation and coagulation activation before and during G-CSF administration. The primary endpoint of the Phase II (efficacy) component of this study is improvement in magnetic resonance imaging (MRI)-determined regional left ventricular contractility and gadolinium distribution (as an index of blood flow) during stress at 1 month following G-CSF administration compared with pretreatment baseline measurements. Secondary Phase II end-points will include determinations of 1) efficacy of stem and endothelial progenitor cell (EPC) mobilization by G-CSF, and 2) changes in treadmill exercise duration associated with G-CSF treatment. Demonstration of safe and effective cytokine-induced mobilization of stem cells with cardiac benefit could result in an important therapeutic option for CAD patients who have few alternatives for the relief of myocardial ischemia and angina pectoris.
