Red cell distribution width as a marker of impaired exercise tolerance in patients with chronic heart failure

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1 European Journal of Heart Failure (2012) 14, doi: /eurjhf/hfr136 Red cell distribution width as a marker of impaired exercise tolerance in patients with chronic heart failure Emeline M. Van Craenenbroeck 1,2 *, Aline J. Pelle 3, Paul J. Beckers 1,2, Nadine M. Possemiers 1,2, Christian Ramakers 4, Christiaan J. Vrints 1,2, Viviane Van Hoof 5, Johan Denollet 3, and Viviane M. Conraads 1,2 1 Department of Cardiology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; 2 Laboratory of Molecular and Cellular Cardiology, Antwerp University Hospital, Edegem, Belgium; 3 Center of Research on Psychology in Somatic diseases (CoRPS), Tilburg University, Tilburg, The Netherlands; 4 Department of Clinical Chemistry, St. Elisabeth Hospital, Tilburg, The Netherlands; and 5 Department of Clinical Chemistry, Antwerp University Hospital, Edegem, Belgium Received 7 June 2011; revised 17 August 2011; accepted 22 September 2011; online publish-ahead-of-print 25 October 2011 Aims Exercise intolerance predicts mortality in patients with chronic heart failure (CHF). Recently, increased red cell distribution width (RDW) has emerged as an additional powerful predictor of poor outcome. We investigated the relationship between RDW and exercise capacity in patients with CHF. In addition, the association between training-induced improved maximal aerobic capacity (VO 2 peak) and RDW was studied.... Methods Stable and optimally treated CHF patients (n ¼ 118) with a left ventricular ejection fraction (LVEF),40% were and results included. RDW and cardiopulmonary exercise testing were obtained at baseline and after 6 months of exercise training (n ¼ 71) or a sedentary lifestyle (n ¼ 47). At baseline, log[rdw] was inversely related to VO 2 peak (P ¼ 0.003), independently of disease severity [LVEF, New York Heart Association class, N-terminal pro brain natriuretic peptide (NT-proBNP)] and haemoglobin. Exercise training was associated with a decrease in RDW compared with controls (P, for interaction), independent of baseline VO 2 peak, haemoglobin, and NT-proBNP levels. The change in RDW after 6 months was significantly related to the change in VO 2 peak (r¼ 0.248, P ¼ 0.009).... Conclusions Higher RDW is independently related to impaired exercise capacity in CHF patients. Increased VO 2 peak following exercise training relates to the observed changes in RDW. Whether increased RDW is a marker of impaired exercise tolerance, or plays a pathophysiological role in impaired oxygen transport, deserves further investigation Keywords Red cell distribution width Chronic heart failure Exercise intolerance Introduction Red cell distribution width (RDW) has recently emerged as a powerful predictor of poor outcome in the general population, 1 in patients with coronary artery disease, 2 4 and in both acute heart failure and chronic heart failure (CHF). 5 8 RDW is a measure of variability in red blood cell size. It is an inexpensive and readily available marker that is routinely reported in automated cell counts. The mechanisms through which high RDW is associated with cardiovascular risk remain poorly understood. Elevated RDW is put forward as an integrated marker of multiple chronic pathophysiological processes. In the setting of CHF, associated co-morbidities, such as nutritional deficiencies, inflammation, renal dysfunction, hepatic congestion, and bone marrow dysfunction, could increase RDW values. 9 Peak oxygen consumption (VO 2 peak) is considered the gold standard to assess exercise capacity. The fact that this measure integrates both cardiac performance and the capacity of peripheral working muscles to extract transported oxygen contributes to its strong and independent prognostic power in patients with CHF. 10 Reduced oxygen-carrying capacity of arterial blood is a significant determinant of VO 2 peak. A recently emerging concept is that * Corresponding author. Tel: , Fax: , emeline.vancraenenbroeck@ua.ac.be Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Red cell distribution width as a marker of impaired exercise tolerance 55 the erythrocyte may represent a sensor of overall and cardiovascular health. 9 Besides their oxygen and carbon dioxide transporting function, red blood cells are scavengers of reactive oxygen and nitrogen species, known to be more abundant in chronic inflammatory conditions such as CHF. To exert these critical functions, adequate deformability and redox balance are necessary. 11 We therefore hypothesized that increased RDW values in CHF patients might be related to exercise intolerance. To address this, we studied the relationship between RDW and maximal aerobic capacity. Secondly, it is well recognized that regular physical activity restores the dysregulated immune system and modifies activated neurohormonal pathways, such as the renin angiotensin aldosterone and the sympathetic nervous system. 12 These mechanisms have been shown to regulate efficient erythropoiesis. 13,14 Therefore, we also investigated whether the multifactorial approach provided by exercise training would affect RDW values. Methods Patients and study design Exercise capacity and RDW were investigated in 118 CHF outpatients. From this cohort, 71 patients had been referred for inclusion in a 6-month exercise training programme, and 47 patients, recruited from the Heart Failure Clinic, served as a control group. Exercise capacity and RDW were reassessed after 6 months for the total cohort. Patients were included if: (i) left ventricular ejection fraction (LVEF) was 40% due to ischaemic or dilated cardiomyopathy; (ii) a full blood count was acquired at the time of assessment of exercise capacity; and (iii) they were stable with regard to symptoms and therapy for at least 1 month. Exclusion criteria were: recent acute coronary syndrome or revascularization ( 3 months); actively listed on the transplant list; exercise limited by angina, arrhythmia, peripheral arterial occlusive disease, or musculoskeletal disease; chronic inflammatory or malignant disease; erythropoietin substitution; recent blood transfusion; or severe renal failure (creatinine clearance,30 ml/min). The study complies with the Declaration of Helsinki, was approved by the local ethics committees, and patients gave written, informed consent. Evaluation of exercise capacity Cardiopulmonary exercise testing (CPET) was performed on a treadmill (Medical Jaeger, Würzburg, Germany) in a non-fasting condition and under medication. A ramp protocol, starting with an equivalent of 20 or 40 W and incremental steps equivalent of 10 or 20 W/min was used. A 12-lead electrocardiogram was recorded continuously, and blood pressure was measured every 2 min. Breath-by-breath gas exchange measurements allowed online determination of ventilation (VE), oxygen uptake (VO 2 ), and carbon dioxide production (VCO 2 ). VO 2 peak was determined as the highest attained VO 2 values during the final 30 s of exercise. The percentage of predicted peak oxygen consumption (%) was calculated using the values reported by Wasserman et al. 15 The anaerobic threshold was defined using the V-slope method. 10 Apart from maximal exercise capacity, other variables with prognostic value were obtained during CPET. Peak circulatory power was calculated as VO 2 peak peak systolic blood pressure (mmhg ml VO 2 kg 21 min 22 ). Oxygen pulse at peak exercise was calculated as the ratio VO 2 peak/heart rate (HR) at VO 2 peak (ml VO 2 kg 21 min 22 / beat). The slope of the relationship between VE and VCO 2 (VE/ VCO 2 slope), as a marker of ventilatory inefficiency, was determined by linear regression. Laboratory assays Fasting venous blood samples were obtained at the time of assessment of exercise capacity. Haemoglobin, mean cellular volume (MCV), and RDW were measured using an ADVIA 2120 Haematology system (Siemens Healthcare Diagnostics) on blood collected in ethylenediamine tetra-acetic acid tubes. The coefficient of variation was 1.08% at a mean RDW value of 17.66%, 1.1% at a mean RDW value of 15.07%, and 1.15% at a mean RDW value of 13.15%. The reference range for normal RDW values was %. Serum iron (Fe), total iron binding capacity (TIBC), and creatinine were measured in serum samples at the time of inclusion by means of a Vitros Fusion Instrument (Ortho Clinical Diagnostics). Transferrin saturation (Fe/TIBC) and creatinine clearance (Cockroft Gault formula) were calculated accordingly. Frozen serum samples were batch analysed for the concentration of NT-proBNP (N-terminal pro brain natriuretic peptide) using a sandwich immunoassay on an Elecsys 2010 (Roche Diagnostics). The analytical range extended from 5 to pg/ml. Exercise training protocol Patients who were referred for exercise training trained in the hospital on an ambulatory basis, three times a week for 60 min, during a period of 6 months. Endurance training intensity was set at 90% of HR at the anaerobic threshold. Depending on patients characteristics, such as severe muscle wasting, dynamic resistive exercises were incorporated in the training programme. 16 Statistical analysis Normality of data was assessed using a one-sided Kolmogorov Smirnov test. Continuous data are expressed as mean (SD) when normally distributed or as median (Q1 Q3) if not. RDW, MCV, and NT-proBNP measures were normalized by natural logarithmic transformation prior to analysis. Baseline characteristics of the two groups were compared using x 2 test and t-test where appropriate. Differences over time between groups (¼interaction) were assessed by univariable two-way repeated measures analysis of variance (ANOVA) on normally distributed or normalized data. Differences over time within each group were assessed by paired samples t-tests. Pearson correlation coefficients were used for bivariate correlations. A stepwise multiple linear regression analysis was used to evaluate independent determinants of VO 2 peak. Multivariable analyses were adjusted for the effects of significant determinants on bivariate correlation analysis. All tests were two-sided, and a P-value of,0.05 was considered statistically significant. All analyses were performed using PASW Statistics 18.0 (SPSS Inc., Chicago, IL, USA). Results Demographic and clinical characteristics Baseline characteristics are shown in Table 1. RDW values ranged from 11.6 to 18.3%, with a quarter of the patients displaying values above the upper normal limit (14.6%). Patients presented with moderate to advanced CHF, as is illustrated by their functional New York Heart Assoctation (NYHA) classification and LVEF. Exercise capacity was moderately impaired, with a VO 2 peak that

3 56 E.M. Van Craenenbroeck et al. Table 1 Baseline clinical characteristics stratified by red cell distribution width below or above the upper limit of normal RDW 14.6%, n 5 90 RDW >14.6%, n 5 28 P-value... Age (years) Gender (% male) Body mass index (kg/m 2 ) Heart failure characteristics NYHA class III IV (%) LVEF (%) Aetiology (% ischaemic) Medication ACE inhibitors/arbs (%) Beta-blockers (%) Diuretics (%) Spironolactone (%) Exercise capacity VO 2 peak (ml kg 21 min 22 ) ,0.005 Percentage predicted VO 2 peak (%) ,0.005 Maximal workload (W) ,0.005 VE/VCO 2 slope Heart rate at maximum (b.p.m.) ,0.005 Haematological parameters RDW (%) 13.2 ( ) 15.3 ( ),0.005 Haemoglobin (g/dl) ,0.005 MCV (fl) 91.5 ( ) 89.1 ( ) 0.04 Biochemical parameters NT-proBNP (pg/ml) Creatinine clearance (ml/min) Serum Fe (mg/dl) TIBC (mg/dl) Transferrin saturation (%) High sensitivity CRP (mg/dl) Data are mean + SD or median (first quartile third quartile) or percentages. P-value for comparison of groups (t-test). ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; Fe, iron; LVEF, left ventricular ejection fraction; MCV, mean cellular volume; NT-proBNP, N-terminal pro brain natriuretic peptide; NYHA, New York Heart Association; RDW, red cell distribution width; TIBC, total iron binding capacity; VE/VCO 2 slope, slope of expired minute ventilation for carbon dioxide output; VO 2 peak, peak oxygen consumption. reached on average 68% of the predicted value. Objective measures of exercise capacity were significantly reduced in patients with RDW values exceeding the upper normal limit. None of the patients was severely anaemic (defined by a haemoglobin level of, 9 g/dl). Association between red cell distribution width and maximal exercise capacity At baseline, log[rdw] correlated negatively with objective measures of maximal exercise capacity (Table 2), such as VO 2 peak, maximal workload, and several VO 2 peak-derived prognostic parameters. In addition, the VE/VCO 2 slope, which is a marker of ventilatory inefficiency and is considered an independent prognostic marker, correlated positively with log[rdw]. To investigate the independent association between RDW and VO 2 peak, a multiple linear regression analysis was performed, correcting for all variables that were related to VO 2 peak in bivariate analysis (Table 3). Log[RDW] remained one of the strongest independent associates of VO 2 peak (b ¼ 0.277, P ¼ 0.003), together with age and VE/VCO 2 slope. Using the same co-variates, multiple regression analysis confirmed log[rdw] as the strongest determinant for maximal workload (b¼ 0.381, P, ). Remarkably, log[rdw] was not independently related to VE/VCO 2 slope (b ¼ 0.091, P ¼ 0.326). Association with exercise training No systematic differences were observed between trained and sedentary control CHF patients concerning age, gender, disease

4 Red cell distribution width as a marker of impaired exercise tolerance 57 Table 2 Bivariate correlations of log[red cell distribution width] with maximal exercise capacity Pearson r P-value... VO 2 peak 0.449, Percentage predicted VO 2 peak VO 2 at anaerobic threshold Maximal workload 0.524, Systolic BP at maximum 0.326, Diastolic BP at maximum Heart rate at maximum 0.362, Oxygen pulse Circulatory power 0.471, VE/VCO 2 slope BP, blood pressure; VE/VCO 2 slope, slope of expired minute ventilation for carbon dioxide output; VO 2 peak, peak oxygen consumption. Table 3 Associates of peak oxygen consumption Bivariate correlation Multiple... regression... Pearson r P-value b P-value... Log[RDW] 0.449, Age 0.480, ,0.001 Haemoglobin Creatinine clearance 0.418, Serum Fe Transferrin saturation NYHA class Log[NT-proBNP] 0.389, VE/VCO 2 slope 0.399, Fe, iron; NT-proBNP, N-terminal pro brain natriuretic peptide; NYHA, New York Heart Association; RDW, red cell distribution width; VE/VCO 2 slope, slope of expired minute ventilation for carbon dioxide output. severity, medical treatment, or exercise capacity (Table 4). Training was associated with a significant improvement in VO 2 peak (+11%, P ¼ ), maximal workload (+35%, P, ), and circulatory power (+8%, P ¼ 0.016). Apart from an increase in maximal exercise capacity, exercise training (Table 5) was also associated with an increase in LVEF (+18%, P ¼ ) and a decrease in NT-proBNP levels ( 27%, P ¼ ). RDW values were significantly lower following exercise training (P ¼ ), whereas haemoglobin levels were not affected (Table 5). A general linear model ANOVA confirmed the independent association of exercise training with a decrease in RDW, after adjustment for associated baseline variables such as VO 2 peak, haemoglobin, and log[nt-probnp] (adjusted R 2 ¼ 0.096, P-value for corrected model ¼ 0.006, P-value for training ¼ ). The training-induced decrease in RDW was positively correlated with the decrease in NT-proBNP (r ¼ 0.252; P ¼ 0.035). However, Table 4 Clinical characteristics of patients in the control and training groups Control Training P-value group group... Age (years) Gender (% male) Body mass index (kg/m 2 ) Heart failure characteristics NYHA class III IV (%) LVEF (%) NT-proBNP ( ) ( ) Aetiology (% ischaemic) Exercise capacity VO 2 peak Maximal workload (W) VE/VCO 2 slope Medication ACE inhibitors/arbs (%) Beta-blockers (%) Diuretics (%) Spironolactone (%) Data are mean + SD or median (first quartile third quartile). P-values are based on t-tests for independent samples. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro brain natriuretic peptide; NYHA, New York Heart Association; VE/VCO 2 slope, slope of expired minute ventilation for carbon dioxide output; VO 2 peak, peak oxygen consumption. even after correction for training-induced improvement in cardiac function (change in NT-proBNP levels, change in LVEF), exercise training was independently associated with the decrease in RDW (adjusted R 2 ¼ 0.112, P-value for corrected model ¼ 0.013, P-value for training ¼ 0.025). The change in RDW after 6 months follow-up was significantly related to the change in VO 2 peak (r ¼ 0.248, P ¼ 0.009) and persisted after correction for change in NT-proBNP levels (r ¼ 0.297, P ¼ 0.011). Post-hoc analyses demonstrated that this inverse relationship was only significant for trained patients (r ¼ 0.242, P ¼ 0.048) and not for sedentary controls (r ¼ 0.063, P ¼ 0.683). Relationship of red cell distribution width to disease severity, haemoglobin, iron status, and high sensitivity CRP (hs-crp) Log[RDW] correlated positively with log[nt-probnp] (r ¼ 0.319, P ¼ 0.001), whereas no significant associations with LVEF were found (P. 0.05). Higher RDW values were associated with lower haemoglobin levels (r ¼ 0.343, P, ), but were not related to MCV and iron status. No correlation was found between log[rdw] and log[hs-crp] (r ¼ 0.104, P ¼ 0.268).

5 58 E.M. Van Craenenbroeck et al. Table 5 Effect of exercise training Control group (n 5 47)... Training group (n 5 71)... P-value Baseline 6 months Baseline 6 months... Echocardiographic measures LVEF (%) * Exercise capacity VO 2 peak (ml kg 21 min 22 ) * Maximal workload (W) *, VE/VCO 2 slope Haematological parameters RDW (%) 13.4 ( ) 13.5 ( ) 13.8 ( ) 13.2 ( )* Haemoglobin (g/dl) Biochemical parameters NT-proBNP (pg/ml) 855 ( ) 965 ( ) 956 ( ) 699 ( )* Serum Fe (mg/dl) TIBC (mg/dl) Transferrin saturation (%) High sensitivity CRP (mg/dl) Data are mean + SD or median (first quartile third quartile). *Different from baseline P, P-values are based on univariable repeated measures ANOVA; log-transformed data were used for NT-proBNP and RDW values. CRP, C-reactive protein; Fe, iron; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro brain natriuretic peptide; RDW, red cell distribution width; TIBC, total iron binding capacity; VE/VCO 2 slope, slope of expired minute ventilation for carbon dioxide output; VO 2 peak, peak oxygen consumption. Discussion The present data are the first to describe the relationship between objective measures of exercise capacity and RDW values in patients with CHF. Higher RDW values were significantly related to impaired exercise tolerance in CHF patients, and this association remained after adjustment for clinical and laboratory determinants such as NYHA class, haemoglobin, and NT-proBNP. Moreover, RDW values were significantly decreased in patients who participated in a structured, supervised exercise training programme. The evolution of RDW was directly associated with the observed increase in VO 2 peak. RDW has gained attention as a new and inexpensive prognostic marker in CHF. Several groups have confirmed the initial report by Felker et al., 5 who described the association between RDW and all-cause mortality in two large data sets of symptomatic CHF patients. In that study, RDW emerged as a more powerful predictor of outcome than widely accepted measures of risk, such as LVEF, NYHA functional class, and renal function. Also, in patients with acute heart failure, RDW turns out to be a useful marker of poor outcome, 6 with a prognostic power that is incremental to that of BNP 17 and regardless of anaemia status. 18 Increased red cell distribution width as a marker of exercise intolerance To our knowledge, our report is the first to link high RDW values to exercise intolerance in CHF patients. Higher RDW values were associated with lower exercise capacity, independent of other widely accepted determinants such as age, haemoglobin, renal function, NYHA class, and NT-proBNP values. In fact, RDW was the second strongest determinant of VO 2 peak, after age. The association between RDW and exercise tolerance was demonstrated for VO 2 peak and maximal workload. In addition, several VO 2 peak-derived prognostic parameters, such as VO 2 at anaerobic threshold, O 2 pulse, and peak circulatory power, were also related to RDW. Overall, high RDW turned out to be a strong and independent associate of poor exercise capacity in CHF patients. Potential mechanisms Elevated RDW in CHF patients results from multiple conditions that culminate in ineffective erythropoiesis or increased red cell destruction. These include nutritional deficiencies leading to anaemia due to iron, vitamin B12 and folate deficiency, renal dysfunction with inadequate erythropoietin production, and a proinflammatory environment that causes bone marrow dysfunction. 9 As such, the currently accepted view is that RDW reflects disease severity and has no hitherto identified pathophysiological role. Consequently, the strong association between RDW and exercise intolerance might reflect underlying disease severity and, hence, might not be causal. In addition, other explanations for impaired exercise capacity, which also cause elevated RDW (i.e. anaemia, iron deficiency, or renal failure leading to haemodilution), may be relevant. It needs to be stressed, however, that in the present study, RDW was associated with low exercise capacity, independent of haemoglobin, iron status, and creatinine clearance. Alternatively, ineffective erythropoiesis, resulting in increased variability of red blood cells, may impair oxygen delivery, either

6 Red cell distribution width as a marker of impaired exercise tolerance 59 through changes in oxygen binding capacity or through rheological abnormalities. As far as we know, however, these data have never been investigated in humans. Amongst the studied prognostic markers, RDW was an independent correlate of VO 2 peak, but not for the VE/VCO 2 slope. Although hypothetical, the relationship between maximal aerobic capacity and RDW may be more than an incidental finding of two prognostic markers pointing in the same direction. Besides their key role in oxygen transport, erythrocytes are increasingly recognized as scavengers of both reactive oxygen and nitrogen species. 11 The latter are found in high abundance in proinflammatory and pro-oxidative conditions, such as CHF. 19 In order to maintain these functions at the tissue level, deformability in the microcirculation is required, which could be hampered in anisocytic red blood cells. Conclusions We identified RDW as a strong and independent marker of maximal exercise capacity in patients with CHF. Measurement of RDW is inexpensive, readily available, and might help in directing the evaluation of functional capacity in this particular population. The observation of increased RDW could also be useful as a marker for individual guidance of both pharmacological and nonpharmacological therapy. Whether increased RDW is simply a marker of impaired exercise tolerance or plays a pathophysiological role in impaired oxygen transport deserves further investigation. Exercise training, being a successful strategy for the improvement of functional capacity, is associated with a reduction of RDW values in CHF, a finding that coincides with improved aerobic capacity. Exercise training In the present study, a 6-month exercise training programme was associated with significantly lower RDW values, whereas haemoglobin levels did not change. The decrease in RDW after 6 months follow-up was significantly related to the increase in VO 2 peak in the trained CHF group. Both mechanistic studies and short-term clinical trials support the concept that exercise training is beneficial in patients with CHF. 20 A dose response analysis of the HF-ACTION trial strongly suggests that with increasing exercise volume, maximal exercise capacity, quality of life, hospital admission, and mortality significantly improve. 21,22 Regular physical exercise is known for its anti-inflammatory and antioxidative properties. Several authors have demonstrated that different training modalities reduce proinflammatory cytokine levels. 23,24 In addition, at the level of the skeletal muscle, regular exercise down-regulates proinflammatory cytokine production and inos (inducible nitric oxide sythase) expression, and has significant antioxidative effects. 25 The suppressive effect of proinflammatory cytokines on the bone marrow and on the formation of erythroid burst-forming units 26 might be neutralized by the anti-inflammatory effects of exercise training. Hypothetically, this could lead to a more efficient erythropoiesis and a decrease in RDW. Investigation of the pathophysiological role of RDW in oxygen transport during exercise should lead to better understanding of the current findings. Limitations The effect of exercise training on RDW values was not studied in a randomized controlled trial, although we realize that such a set up would have strengthened our conclusions. 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