2. Commonly seen 30% of non hospitalized CHF 50% of hospitalized CHF patients Increased mortality Increased morbidity Hospitalization Associated

3. Iron Therapy in Chronic Heart Failure (CHF) most common causes of CHF -coronary artery disease (CAD) -hypertensive heart disease -valve disease

4. In CHF anemia defined as hemoglobin (Hb) levels <

5. In CHF, lower Hb values are usually more prevalent in - older patients ( Low intake of red meat-GIT bleeding) - patients with poor kidney function ( Low EPO) - patients in the more advanced stages of the disease (Elevated cytokines) - or presenting with co morbidities ( Diabetes)

6. Silverberg DS, Wexler D, Blum M et al. The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations. J Am Coll Cardiol 2000;35:1737-1744. Silverberg DS, Wexler D, Sheps D et al. The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol 2001;37:1775-1780 The pioneering work of Silverberg et al. has raised interest in the role of anemia in CHF

7. CHF frequently affects renal function through renal vasoconstriction and renal ischemia, resulting in chronic renal dysfunction and reduced EPO production. mechanism of anemia in CHF EPO renal vasoconstriction

8. -affecting iron stores (GIT Problems) Bleeding due to aspirin administration Polyps – Oesophagitis Reduced iron absorption resulting from atrophic gastritis - haemodilution factors contributing to development of anemia in CHF

9. Affecting EPO production -Diabetes EPO producing cells in kidney may be damaged early by glycosylation -Anti hypertensive medications It has also been speculated that the use of ACE inhibitors Angiotensin Receptor Blocker may inhibit EPO production factors contributing to development of anemia in CHF

10. TNF α - IL6 Cause 4 hematological abnormalities 2 affecting EPO Reduced EPO production in the kidney Reduced activity of EPO in the bone marrow 2 affecting Iron Hepcidin induced failure of iron absorbtion from the GIT induced trapping of iron in iron stores in the macrophages

11. Impaired EPO production induces anemia, which, in turn, exacerbates CHF. The process may develop into a vicious cycle that Silverberg et al. call The "cardio-renal syndrome"

12. Pro-inflammatory cytokines (IL-1, TNFα, IL-6, IFNγ)  EPO production EPO + + Iron  Fas Ag Apoptosis ─ Hepcidin Released From liver By IL6  Fe absorption  Fe transport  Fe availability (EPO-R, Tf, TfR, Ferriportin, DMT-1) ─ve effect Erythropoiesis ACE inhibitors

13. factors contribute to the development of iron deficiency in CHF -poor micronutrient supply of diet -intestinal malabsorption secondary to bowel wall edema -blood loss inherent to aspirin use -In CHF patients with chronic kidney failure, proteinuria may further exacerbate iron deficiency -Besides iron deficiency, insufficient micronutrient supply may also affect folate and vitamin B12 stores.

14. Anemia contribute to Eccentric LVH

15. Non-Hematopoietic biological effects of EPO Reduce apoptosis of the cardiomyocytes oxidative stress and inflammation fibrosis Prevent hypoxic damage functional impairment of the heart Increase neovascularization Improve endothelial dysfunction wound healing Some of these effects are due to the increase in number and activity Of endothelial progenitor cells (EPCs) from the bone marrow

16. Eicosanoids influence the state of tension of the smooth muscles. Depending on the impulse that the smooth muscle cells are exposed to, they change from a state of tension to a state of relaxation and vice versa These signaling molecules thereby have a direct effect on important bodily functions, such as blood pressure regulation breathing intestinal activities.

17. No

18. What a body needs iron for Hormone formation formation of hormones can only occur if a biochemical impulse for their production is sent. This requires enzymes - substances, also known as catalysts these enzymes need iron to do their job

19. Serotonin Dopamine an endorphin, is also often referred to as the “happy hormone.” Like serotonin, dopamine is called a “happy hormone” 8.

20. Melatonin DSIP (Delta Sleep Inducing Peptide) regulates the functioning of what is known as our inner clock produces the deep sleep, an important sleep phase that is responsible for the quality of our nightly recovery.

21. Energy production Each body cell contains a large number of mitochondria We consider them our “power plants” and they use adenosine triphosphate (ATP) to produce the necessary chemical cell energy It is the iron-sulfur molecules, which are the central constituents in the cascade of chemical reactions that results in energy being released in the cells

22. Eicosanoid formation Eicosanoids are our organism’s iron-containing signaling molecules, which directly influence many of our bodily functions a) Effect on smooth muscle tension b) Influence on the stomach c) Effect on the immune system

23. c) Effect on the immune system: The eicosanoids also include leukotrienes. Those are small acid particles in the white blood cells, which are 1.effective in connection with allergic and inflammatory reactions. 2.It is also the function of leukotrienes to “attract” the body’s antibodies to the site of an infection.

25. Before considering using Erythropoietin E valuate other causes of anemia (bleeding) O btain CBC Hgb - RBCs count - MCV- MCH A ssess for adequate iron stores Ferritin 50 ng/ml or more TS 20% or more

26. 100 ng/ml invalid

27. Step 1 Insert the TEST CARD Step 2 Apply the SAMPLE Step 3 Read the RESULT in 2 min

28. Restore the iron needed for Erythropoiesis & other functions Resolution of sever anemia with target Hb 12 g/dl Reduce need for transfusion and or hospitalization Enhance quality of life

30. Initiate therapy with IRON Each 1 gm Hgb require 150 mg of bioavilable iron Calculate iron stors by ferritin test Iron stores should be at least 500 mg

31. Initiate therapy with Erythropoietin 50 IU/Kg/W Recheck Hgb every 2 weeks Till goals of therapy achieved

32. ESA Partial responder Hgb increase less than1gm/dl After 4 weeks check iron stores If iron stores are adequate Increase Epo dose 25% Stop Erythropoietin once target Hg Of 12 g/dl achieved

33. ESA responder Hgb increase 1-2 gm/dl/month with Hgb still less than 12g/dl maintain Epo dose Stop Erythropoietin once target Hgb of 12g/dl achieved

34. March 9, 2007

35. The Hemoglobin Sweet Spot 1112139 Hb g/dL Risk 100% 50%

38. Efficient Absorption 23 times greater than iron salts Absorption is through the heme receptors Aong the GIT Compliant Taken with meals Taken with tea &coffee Not affected by Gastric acidity as it Does not need to change to Ferrous-Ferric- Ferrous Quality Made in Sweden

39. Constipation Cramping Heartburn Nausea

43. Heme Iron Polypeptide Absorbed as ferrous Absorbed from receptors along the GIT Iron is Coated with the heme molecule in GIT No constipation Iron salts Absorbed after changing from Ferric Ferrous Ferrous Absorbed from receptors localized at the duodenum Iron is free in GIT in huge quantity Usually associated with constipation Not affected by gastric acidity Affected by gastric acidity Higher absorption Limited absorption

44. Heme Iron Polypeptide Can be taken with food, Tea or Coffee 10 tablet give 60 mg of elemental iron 10 tablets in 5-10 days No constipation For a pregnant lady to load iron of 800 mg she will take 134 tablet in 2 month (2 tab/day) Each 1 gm of hemoglobin need 150 mg of elemental iron = 25 tablet Can be taken in 13 day Iron salts Taken on empty stomach compared to 60 tablets give 60 mg of elemental iron 60 tablets in 2 month Usually associated with constipation For a pregnant lady to load iron of 800 mg she will take 800 tablet in 26 month (1 tab/day) Each 1 gm of hemoglobin need 150 mg of elemental iron = 150 tablet Can be taken in 5 month =