RED CELL DISTRIBUTION WIDTH A NEW MARKER OF EXERCISE INTOLERANCE IN PATIENTS WITH CHRONIC HEART FAILURE Emeline Van Craenenbroeck, Paul Beckers, Nadine Possemiers, Christiaan Vrints, Viviane Conraads Cardiology Department, Antwerp University Hospital, Belgium Disclosure information: This study is supported by the Fund for Scientific Research (FWO-Flandres)
PROGNOSTICATORS IN CHF Single-term prognosticators: ER and hospital admissions Symptoms at rest Cachexia Hemoglobin, sodium, troponin, creatinine High natriuretic peptides LVEF High < 20% natriuretic peptides Symptomatic arrhythmia s Complex, multivariate models: Heart Failure Survival Score Seattle Heart Failure Model
RED CELL DISTRIBUTION WIDTH (RDW) Red blood cell distribution width, RDW, is a measure of the variation of red blood cell volume (MCV) RDW = Standard deviation of MCV Mean MCV X 100 Reference range 11.6-14.6 %, available as part of the complete blood count Higher RDW values indicate greater variation in size (anisocytosis)
RDW IN CHONIC HEART FAILURE Red cell distribution width as a novel prognostic marker in chronic heart failure. Felker M, et al. J Am Coll Cardiol 2007; 50:40-47
RDW IN CHONIC HEART FAILURE N=1087 Red cell distribution width: an inexpensive and powerful prognostic marker in heart failure. Al-Najjar Y, et al. Eur J Heart Fail 2009; 11:1155-1162
CAUSES OF HIGH RDW VALUES Erythropoiesis Iron deficiency Anemia Iron of deficiency chronic disease B12 Anemia or of folate chronic deficiency disease B12 or folate deficiency Inadequate epo production Inadequate epo production Bone marrow suppression Inflammation Hemoglobinopathies Chronic Heart Failure Elevated RDW RBC Destruction Hemolysis Thrombotic conditions Blood Transfusion
EXERCISE INTOLERANCE IN CHF Stroke volume Chronotropic response VO 2 peak = CO x (CaO 2 -CvO 2 ) Blood supply Muscle mass Metabolic alteration in skeletal muscle Deficient oxygen transport in RBC?
AIMS OF THE STUDY 1. To study the relation between objective parameters of exercise intolerance and RDW in CHF 2. To investigate the effect of exercise training on RDW measures in relation to improved exercise capacity
PATIENTS Inclusion - LVEF 40% - Ischemic or dilated cardiomyopathy - Stable symptoms and medical therapy for 1 mth Exclusion - Recent ACS/revascularization - Exercise limited by angina or arrythmia - Anemia, epo substitution, recent blood transfusion - Severe renal failure - Chronic inflammatory of malignant disease TRAINING GROUP 71 patients referred for exercise training 118 CHF patients CONTROL GROUP 47 patients followed at Heart Failure Clinic
STUDY DESIGN Baseline Maximal cardiopulmonary exercise test (Treadmill) Blood sampling (RDW, Hb, Fe status, NT-proBNP) CONTROL GROUP Sedentary TRAINING GROUP Endurance training (+/- resistive exercises) Target HR 90% of HR at AT In hospital, 3x/week, 1h 6-months Follow-up Maximal cardiopulmonary exercise test (Treadmill) Blood sampling (RDW, Hb, Fe status, NT-proBNP)
PATIENT CHARACTERISTICS AGE (YEARS) 60.6 ± 1.0 GENDER (% MALE) 72 HEART FAILURE CHARACTERISTICS NYHA class I-II (%) 47.5 NYHA class III-IV (%) 52.5 LVEF (%) 25.3 ± 8.7 Etiology (% ischemic) 67.8 NT-proBNP (pg/ml) 860 (427-2264) EXERCISE CAPACITY VO 2 peak (ml.kg -1.min -2 ) 19.1 ± 5.3 Percentage predicted VO2peak (%) 74.9 ± 1.7 Maximal Workload (Watt) 103 ± 3.23 HAEMATOLOGICAL PARAMETERS Hemoglobin (g/dl) 13.3 ± 0.13 MCV (fl) 90.7 (88.6-94.7) RDW (%) 13.6 (12.8-14.6) Leukocytes (x 10 9 /L) 6.8 ± 0.17 BIOCHEMICAL PARAMETERS Creatinine Clearance (ml/min) 65.6 ± 2.5 Serum Fe (µg/dl) 98.5 ± 3.8 TIBC (µg/dl) 325 ± 6.8 Transferrin saturation (%) 31 ± 1.4 MEDICATION ACE/ARB (%) 81.4 Beta-blockers (%) 80.5 Diuretics (%) 83.1 Spironolactone (%) 54.2
RELATION OF RDW WITH EXERCISE CAPACITY PEARSON R P-VALUE AGE (YEARS) 0.172 0.062 BODY MASS INDEX (KG/M 2 ) 0.004 0.967 HEART FAILURE CHARACTERISTICS NYHA class 0.193 0.036 LVEF (%) -0.094 0.31 EXERCISE CAPACITY VO 2 peak (ml.kg -1.min -2 ) -0.449 < 0.00001 VO 2 peak at VT2 (ml.kg -1.min -2 ) -0.374 0.001 Maximal Workload (Watt) - 0.524 < 0.00001 VE/VCO2slope 0.287 0.002 Heart rate at maximum (bpm) - 0.362 < 0.0001 Oxygen pulse (mlvo 2.kg -1.min -2 /beat) -0.201 0.029 Circulatory Power (mmhg. mlvo 2.kg -1.min -2 ) -0.471 < 0.00001 LABORATORY PARAMETERS r = -0.449; p<0.0001 lognt-probnp 0.319 < 0.001 Hemoglobin (g/dl) - 0.343 < 0.00001 logmcv - 0.163 0.079 Serum Fe (µg/dl) - 0.127 0.184 TIBC (µg/dl) 0.054 0.596 Transferrin saturation (%) - 0.09 0.381
PREDICTOR OF EXERCISE CAPACITY VO 2 PEAK VE/VCO 2 SLOPE BETA P-VALUE BETA P-VALUE Age - 0.325 0.001 LogRDW - 0.305 0.001 NYHA class - 0.170 0.065 lognt-probnp - 0.031 0.761 Hemoglobin - 0.071 0.513 Creatinine Clearance 0.186 0.076 Serum Fe 0.275 0.215 Transferrin saturation - 0.087 0.669 Age - 0.124 0.265 LogRDW 0.125 0.250 NYHA class 0.211 0.052 lognt-probnp 0.224 0.066 Hemoglobin 0.176 0.172 Creatinine Clearance - 0.190 0.124 Serum Fe 0.064 0.807 Transferrin saturation - 0.250 0.393 Multiple regression analysis based on significant parameters in the bivariate model RDW is a strong and independent predictor of VO 2 peak RDW is not a predictor of VE/VCO 2 slope
VO 2 peak (ml/kg/min) Maximal Workload (Watt) TRAINING Effect on exercise capacity 23 140 P=0.005 P=0.00001 22 130 21 120 20 110 19 100 18 Baseline Follow-up 90 Baseline Follow-up Control Training
RDW(%) TRAINING Effect on RDW values 14.4 14.2 P=0.0003 14.0 13.8 13.6 6-months exercise training significantly reduces RDW values 13.4 13.2 13.0 Baseline Follow-up Control Training
TRAINING Effect on Hemoglobin and Fe status CONTROL GROUP TRAINING GROUP P-Value Baseline Follow-up Baseline Follow-up HEMATOLOGICAL PARAMETERS RDW (%) 13.6 ± 0.2 13.7 ± 0.2 14.0 ± 0.2 13.3 ± 0.1 0.0003 MCV (%) 92.2 ± 1.0 91.2 ± 1.1 91.8 ± 0.7 92.2 ± 0.6 0.022 Hemoglobin (g/dl) 13.6 ± 0.2 13.4 ± 0.2 13.1 ± 0.2 13.3 ± 0.2 0.126 FE STATUS Serum Fe (ug/ml) 102.4 ± 6.8 98.1 ± 6.5 95.9 ± 4.6 94.5 ± 3.1 0.498 TIBC (ug/ml) 340.1 ± 11.4 342.2 ± 10.2 313.8 ± 8.2 325.4 ± 6.7 0.608 Transferrin saturation (%) 31.4 ± 2.3 29.1± 1.8 30.9 ± 1.8 30.2 ± 1.2 0.236 P-values based on ANOVA repeated measures of log transformed data
TRAINING Improved VO 2 peak correlates with decreased RDW Total Group r=-0.248; p=0.009 Trained Group r=-0.242; p=0.048 Control Training
CONCLUSION Red cell distribution width (RDW) is related to objective parameters of exercise intolerance in CHF patients. This relation is independent of hemoglobin or markers of disease severity A 6-months exercise training program significantly reduces RDW values The decrease in RDW values following exercise training is correlated with an increase in aerobic capacity The causal role of high RDW values in exercise intolerance deserves further investigation