Causes of Anemia in Patients with Heart Failure Adriaan Voors, MD, PhD, Cardiologist Professor of Cardiology, UMC Groningen, Netherlands
Background Anemia is common in patients with CHF Prevalence 15 55% Depends on: - Severity of CHF - Definition of anemia
Survival (%) Anemia in Heart Failure is associated with a higher mortality 100 80 Non-anemia 60 40 Anemia 20 0 10 20 30 40 50 60 Time (months) Van der Meer, 2004 JACC
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
Iron deficiency as major cause of anemia in 37 AHF patients
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
Eur Heart J 2007
Eur Heart J 2007
ECV is an independent predictor of anemia in patients with HF Eur Heart J 2007
Eur Heart J 2008
Hemodilution as a major cause of anemia in 100 CHF pts Eur Heart J 2008
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
Angiotensin II induces hematopoiesis Angiotensin stimulates proliferation of erythroid progenitors cells Losartan abolishes this stimulatory effect Mrug, JCI 1997
Interaction between RAS & hematopoiesis
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
Results Hematopoietic proliferation assay 120 p=0.003 p=0.48 BFU-E (%) 100 80 heart failure + anemia heart failure no-anemia healthy controls 60 0 vd Meer; Circulation 2005
Results 60 p=0.017 50 ACE-activity (U/L) 40 30 20 heart failure + anemia heart failure no-anemia 10 0 vd Meer; Circulation 2005
Results Ac-SDKP levels p=0.018 4 3 p=0.004 Ac - SDKP (nmol/l) 2 1 heart failure + anemia heart failure no-anemia healthy controls 0 vd Meer; Circulation 2005
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
Renal function is an independent predictor of anemia in patients with HF Eur Heart J 2007
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
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
160 Results (erythropoiesis) BFU-E / 10 4 CD34 + cells 140 120 100 80 60 40 20 P=0.015 CHF Control 0 0.02 0.1 0.2 1 2 10 EPO IU/ml
Myeloid culture Results (Myelopoiesis) CHF Control Mixed culture 200 Granulocyte 200 Granulocyte Erythroid Colonies / 10 4 CD34 + cells) 150 100 50 * Monocyte * Colonies / 10 4 CD34 + cells) 150 100 50 Monocyte * * * 0 CFU-G CFU-M 0 CFU-G CFU-M BFU-E * P<0.01 vs control
Results (CHF severity) 1000 R= -0.43 p=0.03 * 100 p=0.03 BFU-E / 10 4 CD34 + cells 100 BFU-E / 10 4 CD34 + cells 80 60 40 20 10 10 1 10 2 10 3 10 4 10 5 NTproBNP (pg/ml) 0 II III IV NYHA class Adusted R 2 0.5 adjusted for age, gender, surgical indication, cardiac medications, Hb and creatinine
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
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
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 (1.04-1.65) 0.022 Creatinine* 1.52 (1.20-1.92) <0.001 NT-proBNP* 1.53 (1.20-2.00) 0.001 stnfr-1* 1.79 (1.39-2.29) <0.001 1.62 (1.24-2.11) <0.001 hscrp* 1.46 (1.10-1.93) 0.008 1.58 (1.09-2.29) 0.016 Epo* 1.77 (1.38-2.27) <0.001 1.47 (1.11-1.93) 0.006 IL6 1.35 (1.10-1.65 0.004 Kleijn et al. Submitted
Inflammation and anemia in HF Kleijn et al. Submitted
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?