Oral Iron Repletion Effects On Oxygen Uptake in Heart Failure

Therapeutic options to further improve functional capacity and symptoms in HF beyond
neurohormonal antagonism are limited. Studies have demonstrated impaired oxidative capacity
of skeletal muscle among HF patients, which may contribute to symptoms of breathlessness and
persistent fatigue.

In addition to its role in erythropoiesis, iron (Fe) plays a critical role in skeletal
muscle's oxygen (O2)-storage capacity (myoglobin) and systemic aerobic energy production. As
Fe deficiency is common in patients with symptomatic HF, repletion of iron stores may
improve submaximal exercise capacity among these patients beyond the effects on
erythropoiesis.

While intravenous Fe repletion in HF patients with mild Fe-deficiency (i.e. Ferritin <100 or
Ferritin 100-299 with transferrin saturation <20%) with or without anemia global well-being
and functional status, oral Fe repletion has not been studied. Furthermore, the efficacy of
oral Fe to replete iron stores in a similar population and its impact on functional
capacity, measured objectively by peak VO2, remains unknown.

Inclusion Criteria:

1. Age >18 years

2. Previous clinical diagnosis of heart failure with current NYHA Class II-IV symptoms
LVEF≤0.40 within 2 years prior to consent, and ≥3 months after a major change in
cardiac status (i.e. CABG or CRT).

3. Serum ferritin between 15-100 ng/ml or serum ferritin between 100-299 ng/ml with
transferrin saturation <20%

4. Hemoglobin 9.0-13.5 g/dL (males), 9-13.5 (females) at time of enrollment

5. Stable evidence-based medical therapy for HF (including beta-blocker and
ACE-inhibitor/ARB unless previously deemed intolerant, and diuretics as necessary)
with
a. Changes in diuretic dose guided by a patient-directed flexible dosing program are
considered stable medical therapy

6. Willingness to provide informed consent

Exclusion Criteria:

1. Presence of a neuromuscular, orthopedic or other non-cardiac condition that prevents
the patient from exercise testing on a bicycle/treadmill ergometer and/or inability
to achieve an RER ≥ 1.0 on screening/baseline CPET

2. Severe renal dysfunction (eGFR< 20 ml/min/1.73m2)

3. Severe liver disease (ALT or AST > 3x normal, alkaline phosphatase or bilirubin >2x
normal)

4. Gastrointestinal conditions known to impair Fe absorption (i.e. inflammatory bowel
disease)

5. Known active infection as defined by current use of oral or intravenous antimicrobial
agents

6. Documented active gastrointestinal bleeding

7. Active malignancy other than non-melanoma skin cancers

8. Anemia with known cause other than Fe deficiency or chronic disease

9. Fe overload disorders (i.e. hemochromatosis or hemosiderosis)

10. History of erythropoietin, IV or oral Fe therapy, or blood transfusion in previous 3
months.

11. Current ventricular assist device

12. Anticipated cardiac transplantation within the next 4 months

13. Primary hypertrophic cardiomyopathy, infiltrative cardiomyopathy, acute myocarditis,
constrictive pericarditis or tamponade

14. Previous adverse reaction to study drug or other oral Fe preparation

15. Known or anticipated pregnancy in the next 4 months