Background-Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries. Methods and Results-Here we show that chronic treatment with bone marrow-derived progenitor cells from young nonatherosclerotic ApoE Ϫ/Ϫ mice prevents atherosclerosis progression in ApoE Ϫ/Ϫ recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE Ϫ/Ϫ mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE Ϫ/Ϫ mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury. Conclusions-Our

Erythropoietin (EPO) has been shown to protect neurons from ischemic stroke, but can also increase thrombotic events and mortality rates in patients with ischemic heart disease. We reasoned that benefits of EPO might be offset by increases in hematocrit and evaluated the direct effects of EPO in the ischemic heart. We show that preconditioning with EPO protects H9c2 myoblasts in vitro and cardiomyocytes in vivo against ischemic injury. EPO treatment leads to significantly improved cardiac function following myocardial infarction. This protection is associated with mitigation of myocyte apoptosis, translating into more viable myocardium and less ventricular dysfunction. EPO-mediated myocyte survival appears to involve Akt activation. Importantly, cardioprotective effects of EPO were seen without an increase in hematocrit (eliminating oxygen delivery as an etiologic factor in myocyte survival and function), demonstrating that EPO can directly protect the ischemic and infarcted heart. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: myocardial infarction (MI); erythropoietin (EPO); erythropoietin receptor (EPO-R); Janus-associated kinase-2 (Jak2); trichloroacetic acid (TCA); left circumflex coronary artery (LCx); reactive oxygen species (ROS); left ventricle (LV); triphenyltetrazolium chloride (TTC); β-adrenergic receptor (βAR); LV end-diastolic pressure (LVEDP).

Background-Single-bolus intracoronary administration of fibroblast growth factor-2 (FGF2) improved symptoms and myocardial function in a phase I, open-label trial in patients with coronary artery disease. We conducted the FGF Initiating RevaScularization Trial (FIRST) to evaluate further the efficacy and safety of recombinant FGF2 (rFGF2). Methods and Results-FIRST is a multicenter, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of rFGF2 at 0, 0.3, 3, or 30 g/kg (nϭ337 patients). Efficacy was evaluated at 90 and 180 days by exercise tolerance test, myocardial nuclear perfusion imaging, Seattle Angina Questionnaire, and Short-Form 36 questionnaire. Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. rFGF2 reduced angina symptoms as measured by the angina frequency score of the Seattle Angina Questionnaire (overall Pϭ0.035) and the physical component summary scale of the Short-Form 36 (pairwise Pϭ0.033, all FGF groups versus placebo). These differences were more pronounced in highly symptomatic patients (baseline angina frequency score Յ40 or Canadian Cardiovascular Society score of III or IV). None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the 30-g/kg rFGF2 group.