The purpose of this study is to determine if treating anemia with subcutaneous erythropoetin in patients with heart failure and a preserved ejection fraction (HFPEF) will be associated with reverse ventricular remodeling, significant improvements in exercise capacity, and improved health status, as compared with placebo.

Heart failure frequently occurs in patients with a preserved ejection fraction (HFPEF) and affected subjects are predominantly elderly women with several co-morbid conditions. Despite the diversity of underlying clinical pathologies and co-morbid conditions present in these patients, a common pathophysiologic explanation is generally applied to explain their clinical symptoms. Our preliminary data show that a significant subgroup with HFPEF has increases in ventricular volumes and expanded plasma volumes, consistent with a volume overloaded state. In the setting of a preserved EF with end diastolic volume increased, stroke volume must increase, indicating a high output state. Anemia may be an important, modifiable contributor to the observed high output and volume overload as well as exercise intolerance in elderly HFPEF patients, abnormal ventricular remodeling and impaired overall health status and quality of life. This protocol evaluates the impact of treating anemia in subjects with HFPEF. The specific aims of the current study are to provide a comprehensive and mechanistically based assessment of how correcting anemia in subjects with HFPEF can impact on functional capacity, ventricular structure and function and overall health status. We propose to perform a randomized, prospective, double blind study in 80 subjects with HFPEF to test the hypothesis that the administration of subcutaneous erythropoietin will be associated with reverse ventricular remodeling, significant improvements in exercise capacity and improved health status.

Inclusion Criteria:

1. Heart failure and a preserved ejection fraction (HFPEF) - EF >=40%
2. Anemia - defined as hemoglobin < 12 g/dL
3. Age >= 55 years
4. Patients must be able to understand and sign the informed consent document after the nature of the study has been fully explained, prior to beginning any study procedures.

Exclusion Criteria:

1. Presence of uncontrolled hypertension (Systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 90 mm Hg)
2. Resting heart rate > 120 bpm
3. Baseline 6-minute walk test > 450 meters
4. Valvular heart disease (e.g. more than mild regurgitant or stenotic mitral, aortic, tricuspid, or pulmonic valve disease).
5. Infiltrative cardiac disease such as hemochromatosis and amyloidosis
6. Hypertrophic cardiomyopathy
7. Chronic pulmonary disease (FEV 1 < 60% predicted)
8. Renal failure (GFR < 15 ml/min)
9. Hemoglobin < 8 g/dL
10. BMI > 40
11. Exercise limited by angina, claudication, orthopedic, or neurological diseases.
12. Severe liver dysfunction that is defined by an international normalized ratio > 2.0, not caused by an anticoagulant.
13. Current or recent treatment (within past 6 months) with erythropoietin
14. Erythropoietin level > 100 mU/ml
15. Recent cardiac surgery (< 3 months)
16. Known iron deficiency anemia from chronic GI blood loss, uterine bleeding, or other chronic bleeding
17. Planned surgery during the course of the study
18. Significant alcohol use or illicit drug use.
19. Patients with a known hypercoagulable state.
20. Active hematologic disease (e.g. sickle cell anemia, thalassemia, chronic myelogenous leukemia) or malignancy
21. Patients with current seizure disorder or activity
22. Patients who are known to be pregnant
23. History of deep venous thrombosis (DVT) or pulmonary embolus (PE) within 12 months before study entry. Prior superficial thrombophlebitis is not an exclusion criterion.
24. History of cerebrovascular accident (CVA) within 6 months
25. History of transient ischemic attack (TIA) within 6 months
26. History of acute coronary syndrome (ACS), or other arterial thrombosis within 6 months before study entry. ACS includes unstable angina, Q wave myocardial infarction (QwMI), and non-Q wave myocardial infarction (NQMI).
27. Allergy or sensitivity to human serum albumin
28. Known hypersensitivity to mammalian cell-derived products