Stem Cell Mobilization to Treat Chest Pain and Shortness of Breath in Patients With Coronary Artery Disease

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.

Inclusion criteria

Adults older than 21 years.

Functional class (CCS) 3 or 4 angina attributable to atherosclerotic CAD, despite medical management, not optimal for mechanical revascularization due to coronary anatomy, co-morbidity, or patient preference.

Left ventricular ejection fraction greater than 30 percent.

Inducible myocardial ischemia by dobutamine stress MRI.

No congestive heart failure symptoms within 2 months.

No active infection.

Normal renal function:creatinine less than 1.5 mg/dl, proteinuria less than 1plus

Normal liver function: bilirubin less than 1.5 mg/dl, transaminases within normal limits.

Normal blood count: WBC 3000-10000/microliter, granulocytes greater than 1500/microliter; platelet count greater than 150,000/microliter, Hgb greater than 12.5 g/dl.

Subject understands protocol and provides written, informed consent in addition to willingness to comply with specified follow-up evaluations.

Exclusion criteria

Myocardial infarction within 2 months.

Crescendo angina: Angina pectoris that is prolonged in duration (greater than 30 minutes), does not respond to nitroglycerin (3 tablets), or is occurring with increasing frequency over the previous two weeks.

Significant structural heart disease (e.g. hypertrophic or dilated cardiomyopathy, valvular heart disease) as determined by echocardiography.

Patients who are HIV positive, have chronic inflammatory diseases, or are on chronic immunosuppressive medications.

Women of childbearing age unless recent pregnancy test is negative.

Lactating women.

Known active malignancy or prior history of hematologic malignancy.

Participation in unrelated research involving an investigational pharmacological agent 30 days before planned G-CSF dosing.

Contraindication for MRI.

Known hypersensitivity to E. coli-derived proteins or to gadolinium.