Causes of Anemia in Patients with Heart Failure. Adriaan Voors, MD, PhD, Cardiologist Professor of Cardiology, UMC Groningen, Netherlands

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1 Causes of Anemia in Patients with Heart Failure Adriaan Voors, MD, PhD, Cardiologist Professor of Cardiology, UMC Groningen, Netherlands

2 Background Anemia is common in patients with CHF Prevalence 15 55% Depends on: - Severity of CHF - Definition of anemia

3 Survival (%) Anemia in Heart Failure is associated with a higher mortality Non-anemia Anemia Time (months) Van der Meer, 2004 JACC

4 Possible etiologies of anemia in HF Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Voors. Eur Heart J. 2004

5 Iron deficiency as major cause of anemia in 37 AHF patients

6 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Voors. Eur Heart J. 2004

7 Eur Heart J 2007

8 Eur Heart J 2007

9 ECV is an independent predictor of anemia in patients with HF Eur Heart J 2007

10 Eur Heart J 2008

11 Hemodilution as a major cause of anemia in 100 CHF pts Eur Heart J 2008

12 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Eur Heart J. 2004

13 Angiotensin II induces hematopoiesis Angiotensin stimulates proliferation of erythroid progenitors cells Losartan abolishes this stimulatory effect Mrug, JCI 1997

14 Interaction between RAS & hematopoiesis

15 Methods Population: 108 patients were included in this study 17 anemic HF patients (10 unexplained no hematinic abnormalities and no renal failure) 81 non-anemic HF patients 10 age-matched healthy controls All HF patients were in NYHA III All HF patients were using ACE-inhibitors Definition anemia (WHO): Males: Hemoglobin <8.1 mmol/l Females: Hemoglobin < 7.5 mmol/l vd Meer; Circulation 2005

16 Results Hematopoietic proliferation assay 120 p=0.003 p=0.48 BFU-E (%) heart failure + anemia heart failure no-anemia healthy controls 60 0 vd Meer; Circulation 2005

17 Results 60 p= ACE-activity (U/L) heart failure + anemia heart failure no-anemia 10 0 vd Meer; Circulation 2005

18 Results Ac-SDKP levels p= p=0.004 Ac - SDKP (nmol/l) 2 1 heart failure + anemia heart failure no-anemia healthy controls 0 vd Meer; Circulation 2005

19 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Voors. Eur Heart J. 2004

20 Renal function is an independent predictor of anemia in patients with HF Eur Heart J 2007

21 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Voors. Eur Heart J. 2004

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23 Methods Patients 20 CHF patients (Age 67 years, LVEF 32%, 35% anemia) 20 age and gender matched controls (LVEF>50) Methods Bone marrow harvested from sternum during cardiac surgery Immunomagnetically isolated CD34 + hematopoietic progenitor cells in Erythroid lineage culture (incrementing doses of EPO) Myeloid culture (GM-CSF + IL-3) Mixed culture (SCF, EPO, IL-6, GM-CSF, IL-3) Correlation with the severity of CHF

24 160 Results (erythropoiesis) BFU-E / 10 4 CD34 + cells P=0.015 CHF Control EPO IU/ml

25 Myeloid culture Results (Myelopoiesis) CHF Control Mixed culture 200 Granulocyte 200 Granulocyte Erythroid Colonies / 10 4 CD34 + cells) * Monocyte * Colonies / 10 4 CD34 + cells) Monocyte * * * 0 CFU-G CFU-M 0 CFU-G CFU-M BFU-E * P<0.01 vs control

26 Results (CHF severity) 1000 R= p=0.03 * 100 p=0.03 BFU-E / 10 4 CD34 + cells 100 BFU-E / 10 4 CD34 + cells NTproBNP (pg/ml) 0 II III IV NYHA class Adusted R adjusted for age, gender, surgical indication, cardiac medications, Hb and creatinine

27 Possible etiologies of anemia in heart failure Bone marrow - Insensitivity to EPO - Cytokines (TNF ) Malnutrition - Low iron - Vitamine B11,B12 Renal failure - EPO production Anemia Chronic blood loss - Use of Anticoagulation Medication - Use of ACE-inhibitors/ARB Hemodilution Van der Meer, Eur Heart J. 2004

28 Inflammation and anemia in HF 326 CHF patients; Hb, Ht, hscrp, IL-6, stnfr-1, EPO primary endpoint was all-cause mortality. FU was 18 months. Kleijn et al. Submitted

29 Inflammation and anemia in HF Logistic regression analysis; independent predictors of anaemia at baseline Variable Univariable Multivariable OR (95% CI) p-value OR (95% CI) p-value Age 1.31 ( ) Creatinine* 1.52 ( ) <0.001 NT-proBNP* 1.53 ( ) stnfr-1* 1.79 ( ) < ( ) <0.001 hscrp* 1.46 ( ) ( ) Epo* 1.77 ( ) < ( ) IL ( Kleijn et al. Submitted

30 Inflammation and anemia in HF Kleijn et al. Submitted

31 Conclusions Lower hemoglobin levels often seen in HF patients and related to a poorer prognosis Multiple factors are involved, such as iron deficiency, hemodilution, ACEinhibitor, renal dysfunction, bone marrow dysfunction, and inflammation Anemia sign of poor clinical status or causative for poor outcome?