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Usefulness of Red Cell Distribution Width as a Prognostic Marker in Pulmonary Hypertension

      Red blood cell distribution width (RDW), a widely available biomarker, independently predicts adverse outcomes in left-sided heart failure. The relation between RDW and death in pulmonary hypertension (PH) is unknown. In a prospective study of 162 consecutive patients with PH, RDW was recorded during initial diagnostic right-sided cardiac catheterization, and patients were followed for 2.1 ± 0.8 years to determine vital status. Demographic, clinical, laboratory, and hemodynamic variables were compared by tertile of RDW. Cox proportional-hazards models were used to determine whether RDW was independently associated with death, and the prognostic utility of RDW was compared to that of other laboratory predictors, including N-terminal–pro–B-type natriuretic peptide (NT–pro-BNP). Of the 162 study patients, 78% were women, and 62% had pulmonary arterial hypertension. The mean age was 53 ± 15 years, and most patients had severe PH (mean pulmonary artery pressure 48 ± 13 mm Hg). The highest tertile of RDW predicted death (univariate hazard ratio 4.86, 95% confidence interval 1.37 to 17.29, p = 0.015; multivariate hazard ratio 2.4, 95% confidence interval 1.02 to 5.84, p = 0.045, after adjusting for age, gender, diabetes mellitus, connective tissue disease, diuretic use, phosphodiesterase inhibitor use, hemoglobin, mean corpuscular volume, and blood urea nitrogen [BUN]). Of the laboratory data, only RDW, BUN, and NT–pro-BNP were associated with death on univariate analysis. When RDW, BUN, and NT–pro-BNP were entered into a multivariate model, only RDW was still associated with death (p = 0.037 for RDW, p = 0.18 for BUN, and p = 0.39 for NT–pro-BNP). Adding NT–pro-BNP to RDW did not improve the prediction of mortality. In conclusion, RDW is independently associated with death in patients with PH and performs better as a prognostic indicator than NT–pro-BNP.
      The identification of new prognostic markers may identify at-risk patients early and may provide insight into therapeutic avenues for patients with pulmonary hypertension (PH).
      • McLaughlin V.V.
      • Presberg K.W.
      • Doyle R.L.
      • Abman S.H.
      • McCrory D.C.
      • Fortin T.
      • Ahearn G.
      Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
      A variety of such markers have been used to create predictive models for survival in patients with chronic left-sided heart failure.
      • Levy W.C.
      • Mozaffarian D.
      • Linker D.T.
      • Sutradhar S.C.
      • Anker S.D.
      • Cropp A.B.
      • Anand I.
      • Maggioni A.
      • Burton P.
      • Sullivan M.D.
      • Pitt B.
      • Poole-Wilson P.A.
      • Mann D.L.
      • Packer M.
      The Seattle Heart Failure Model: prediction of survival in heart failure.
      • Pocock S.J.
      • Wang D.
      • Pfeffer M.A.
      • Yusuf S.
      • McMurray J.J.
      • Swedberg K.B.
      • Ostergren J.
      • Michelson E.L.
      • Pieper K.S.
      • Granger C.B.
      Predictors of mortality and morbidity in patients with chronic heart failure.
      Red blood cell distribution width (RDW), one such marker, reflects the variability in the size of circulating red blood cells and is routinely reported in automated complete blood counts. Felker et al
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      reported an independent association between RDW and the risk for adverse outcomes in patients with left-sided heart failure, even after adjusting for hemoglobin. Furthermore, a more recent study found a graded independent relation between higher levels of RDW and the risk for heart failure, cardiovascular events, and all-cause mortality in patients with previous myocardial infarction but no evidence of heart failure at baseline.
      • Tonelli M.
      • Sacks F.
      • Arnold M.
      • Moye L.
      • Davis B.
      • Pfeffer M.
      Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease.
      To our knowledge, RDW has never been studied in PH. On the basis of our anecdotal experience that increased RDW is associated with worse outcomes in PH, we hypothesized that RDW would be independently associated with increased mortality in PH. We therefore conducted a prospective evaluation of the prognostic value of RDW in patients with PH.

      Methods

      We studied patients in the Pulmonary Hypertension Connection (PHC) registry, which was initiated in March 2004 and has been described in detail previously.
      • Thenappan T.
      • Shah S.J.
      • Rich S.
      • Gomberg-Maitland M.
      A USA-based registry for pulmonary arterial hypertension: 1982–2006.
      For the purposes of the present study, we evaluated only patients entered into the PHC registry prospectively (all patients were evaluated at the University of Chicago Medical Center).
      In the PHC registry, only 2 investigators with expertise in data management and understanding of clinical care of patients with PH entered the data. Neither of these investigators participated in the care of the patients in the registry, and neither had knowledge of the hypothesis of the present study. A third investigator (blinded to all other clinical and outcome data) collected data on laboratory tests (including RDW) that were performed on the day of cardiac catheterization. Informed consent for participation in the registry was obtained during initial evaluation for all patients. The PHC registry was approved by the institutional review board at the University of Chicago.
      A total of 162 consecutive adult patients (aged ≥18 years) who were entered prospectively into the PHC registry were studied, all of whom had RDW measurement available on the day of cardiac catheterization. The date of cardiac catheterization served as the enrollment date for our prospective study. We collected clinical information, exercise capacity, laboratory data, and cardiac catheterization data on all 162 patients. Obesity was defined as present for body mass index >30 kg/m2, and coronary artery disease was recorded as present if there was a clinical history of coronary artery disease, abnormal stress test results with evidence of ischemia, or documented coronary stenosis >50%. Baseline RDW was measured using a Beckman Coulter Automated CBC Analyzer (Beckman Coulter, Inc., Fullerton, California). The normal reference range for RDW in our laboratory is <15.0%. N-terminal–pro–B-type natriuretic peptide (NT–pro-BNP), which has previously been identified as a prognostic marker in PH,
      • Fijalkowska A.
      • Kurzyna M.
      • Torbicki A.
      • Szewczyk G.
      • Florczyk M.
      • Pruszczyk P.
      • Szturmowicz M.
      Serum N-terminal brain natriuretic peptide as a prognostic parameter in patients with pulmonary hypertension.
      was measured using the Elecsys proBNP immunoassay (Roche Diagnostics GmbH, Basel, Switzerland). The normal reference ranges for NT–pro-BNP in our laboratory are <125 pg/ml for patients aged <75 years and <450 pg/ml for those aged >75 years. All 162 subjects included in our analysis underwent baseline hemodynamic testing by cardiac catheterization.
      Vital statistics were collected for all patients by chart review and by query of the Social Security Death Index. For each death, the cause and date of death were documented. Social Security Death Index data were available on all patients. In all patients who were not identified as deceased in the Social Security Death Index, we were able to confirm vital status by chart review. Patients were followed for 2.1 ± 0.8 years, and mortality data were ascertained on all patients.
      All continuous variables are expressed as mean ± SD unless otherwise noted, and p values <0.05 were considered statistically significant. We divided RDW into tertiles and compared demographics, clinical characteristics, laboratory test results, and hemodynamics with analysis of variance and Kruskal-Wallis tests for continuous variables and chi-square and Fisher's exact tests for categorical variables. We then used univariate and backward-selection multivariate Cox proportional-hazards models to determine whether RDW was independently associated with death. The referent group in all Cox models was the lowest RDW tertile. Variables associated with RDW at p <0.05 were included in our multivariate models, and right-skewed variables were log transformed to attain a normal distribution before inclusion into multivariate models. Given the limited number of outcome events, we repeated our multivariate analysis with a more parsimonious model that included only diuretic use, hemoglobin, and log-transformed blood urea nitrogen (BUN) as covariates. The proportional-hazards assumption was tested and confirmed for all Cox regression models. Next, we analyzed RDW and other routine laboratory tests, including NT–pro-BNP, using Cox regression models to determine which tests were associated with death. To determine the relative utility of laboratory tests as prognostic indicators, Cox regression models were compared using the likelihood ratio test. All statistical analyses were performed using Stata version 9 (StataCorp LP, College Station, Texas).

      Results

      Of the 162 study patients, 78% were women, and 62% had World Health Organization category I PH (pulmonary arterial hypertension). The mean age was 53 ± 15 years. Overall, patients in the study cohort had severe PH (right atrial pressure 11 ± 7 mm Hg, mean pulmonary artery pressure 48 ± 13 mm Hg, cardiac index 2.5 ± 1.0 L/min/m2, and pulmonary vascular resistance 9.6 ± 6.2 Wood units) and poor functional status (87% had World Health Organization functional class III or IV symptoms). The mean RDW was 16.5 ± 2.5% (median RDW 15.9%, interquartile range 14.7% to 18.1%). Table 1 lists differences in clinical characteristics among the 3 tertiles of RDW. None of the World Health Organization categories of PH were associated with RDW tertile. However, within World Health Organization category I PH (pulmonary arterial hypertension), patients in the highest tertile of RDW were more likely to have connective tissue disease (33% in tertile III vs 22% in tertile II vs 10% in tertile I, p = 0.013). None of the invasive hemodynamic variables were associated with RDW tertile. However, we did find a loose correlation between RDW and right atrial pressure (r = 0.20, p = 0.012). RDW did not correlate with any other invasive hemodynamic variable. RDW was negatively correlated with hemoglobin (r = −0.25, p = 0.0013), hematocrit (r = −0.24, p = 0.0017), and mean corpuscular volume (r = −0.42, p <0.0001).
      Table 1Baseline demographic, clinical, laboratory, echocardiographic, and hemodynamic characteristics by tertile of red cell distribution width
      CharacteristicsRDW Tertilep Value
      IIIIII
      (n = 52)(n = 55)(n = 55)
      RDW (%)14.1 ± 0.6 (12.7–14.9)15.9 ± 0.6 (15.0–17.1)19.5 ± 1.7 (17.4–24.5)
      Age (years)49 ± 1553 ± 1555 ± 140.10
      Women37 (71%)43 (78%)47 (85%)0.20
      Cause of pulmonary hypertension0.22
      Overall Fisher's exact test for all 4 categories.
       WHO category I (pulmonary arterial hypertension)31 (60%)37 (67%)32 (58%)
       WHO category II (pulmonary venous hypertension)9 (17%)10 (18%)15 (27%)
       WHO category III (PH associated with hypoxemia)2 (4%)2 (4%)1 (2%)
       WHO category IV (PH due to chronic thromboembolic disease)3 (6%)4 (7%)0 (0%)
       WHO category V (miscellaneous)7 (13%)2 (4%)7 (13%)
      Medications
       Diuretics22 (42%)39 (71%)41 (75%)0.001
       Calcium channel blockers19 (37%)14 (25%)16 (29%)0.45
       Digoxin5 (10%)7 (13%)9 (16%)0.64
       Warfarin14 (27%)19 (34%)19 (34%)0.63
       Prostacyclins1 (2%)0 (0%)1 (2%)0.77
       Endothelin blockers7 (13%)7 (13%)4 (7%)0.55
       Phosphodiesterase inhibitors3 (6%)2 (4%)9 (16%)0.049
      Co-morbidities
       Systemic hypertension18 (35%)24 (44%)27 (50%)0.28
       Diabetes mellitus3 (6%)12 (22%)11 (20%)0.037
       Obesity18 (35%)22 (40%)18 (33%)0.71
       Coronary artery disease3 (6%)4 (7%)7 (13%)0.47
      Oxygen use6 (12%)12 (22%)11 (20%)0.34
      WHO functional class0.89
      Overall Fisher's exact test for all 4 categories.
       I2 (4%)3 (6%)2 (4%)
       II3 (6%)6 (12%)4 (9%)
       III31 (62%)25 (48%)28 (54%)
       IV14 (28%)18 (35%)15 (33%)
      Laboratory tests
       White blood cell count (103/mm3)8 ± 58 ± 28 ± 30.94
       Hemoglobin (g/dl)15 ± 513 ± 213 ± 30.002
       Hematocrit (%)43 ± 642 ± 639 ± 70.008
       Mean corpuscular volume (μm3)91 ± 589 ± 583 ± 12<0.0001
       Platelet count (103/mm3)233 ± 83232 ± 90256 ± 1130.34
       Sodium (mmol/L)140 ± 3138 ± 5138 ± 40.053
       BUN (mg/dl)15 (12–19.5)17 (13–23)23 (14–35)0.005
       Creatinine (mg/dl)0.91 ± 0.251.10 ± 0.631.12 ± 0.430.052
       NT–pro-BNP (pg/ml)453 (176–1,553)1,500 (477–3,386)1,436 (259–3,672)0.063
      Treadmill exercise capacity (METs)3.9 ± 1.83.9 ± 2.43.2 ± 1.70.45
      Hemodynamics
       Mean right atrial pressure (mm Hg)9 ± 611 ± 711 ± 70.13
       Mean pulmonary artery pressure (mm Hg)47 ± 1749 ± 1146 ± 100.43
       Cardiac index (L/min/m2)2.5 ± 0.92.4 ± 0.82.5 ± 1.10.66
       Pulmonary capillary wedge pressure (mm Hg)12 ± 512 ± 813 ± 70.85
       Pulmonary vascular resistance (Wood units)9.8 ± 7.39.5 ± 4.49.4 ± 6.90.97
       Mean aortic pressure (mm Hg)95 ± 1791 ± 1489 ± 150.22
       Aortic oxygen saturation (%)91 ± 592 ± 591 ± 80.92
      Data are expressed as mean ± SD, as number (percentage), or as median (interquartile range).
      WHO = World Health Organization.
      low asterisk Overall Fisher's exact test for all 4 categories.
      During a mean follow-up period of 2.1 ± 0.8 years, 22 of 162 of the patients (14%) died. Death was due to PH in 50% of the subjects. Other causes of death included sepsis and underlying cause of PH (e.g., systemic sclerosis, cirrhosis, parenchymal lung disease). Patients who died had higher baseline RDW values (17.8 ± 2.6% vs 16.3 ± 2.4%, p = 0.011; Figure 1). There was also a graded increase in mortality rate with each RDW tertile: 6% in tertile I, 13% in tertile II, and 22% in tertile III. Before computing survival analyses, we log transformed NT–pro-BNP and BUN because these 2 variables were right skewed. Hemoglobin and hematocrit were highly correlated (r = 0.68, p <0.0001). Therefore, only hemoglobin was retained in the multivariate Cox models. On Cox regression analysis, the highest tertile of RDW predicted death (univariate hazard ratio [HR] 4.86, 95% confidence interval [CI] 1.37 to 17.29, p = 0.015; multivariate HR 2.4, 95% CI 1.02 to 5.84, p = 0.045, after adjusting for age, gender, diabetes mellitus, connective tissue disease, diuretic use, phosphodiesterase inhibitor use, hemoglobin, mean corpuscular volume, and log BUN). The middle RDW tertile was also associated with an increased hazard of death (univariate HR 2.5, 95% CI 0.6 to 9.6; multivariate HR 2.0, 95% CI 0.5 to 8.0), although the CIs overlapped with 1 (univariate p = 0.19, multivariate p = 0.32). Figure 2 displays the cumulative survival by tertile of RDW. In a more parsimonious multivariate model (with diuretic use, hemoglobin, and log BUN as the only covariates), the highest tertile of RDW was still associated with death (HR 3.9, 95% CI 1.0 to 14.3, p = 0.044).
      Figure thumbnail gr1
      Figure 1Comparison of baseline RDW values: alive versus deceased (p = 0.011).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier survival curves by RDW tertile (log-rank p = 0.013).
      Table 2 lists the HRs (per SD increase) of various routine laboratory values and indicates that only RDW, BUN, and NT–pro-BNP were associated with an increased hazard of death on univariate analysis. When RDW, log-transformed BUN, and log-transformed NT–pro-BNP (all continuous variables) were entered into a multivariate Cox model, only RDW was still associated with death (p = 0.037 for RDW, p = 0.18 for BUN, and p = 0.39 for NT–pro-BNP). Table 3 demonstrates that adding NT–pro-BNP to RDW did not improve the prediction of mortality, whereas adding BUN marginally improved risk prediction.
      Table 2Univariate hazard ratios for routine laboratory tests as predictors of mortality
      PredictorUnivariate HR (95% CI)
      HRs correspond to an SD increase in the predictor variable.
      p Value
      RDW1.63 (1.16–2.30)0.005
      Sodium0.81 (0.61–1.08)0.15
      Log BUN1.82 (1.21–2.76)0.004
      Creatinine1.12 (0.85–1.47)0.41
      Log NT–pro-BNP1.62 (1.01–2.60)0.044
      White blood cell count1.41 (0.84–2.39)0.20
      Hemoglobin0.77 (0.42–1.42)0.41
      Hematocrit0.92 (0.61–1.40)0.71
      Mean corpuscular volume0.88 (0.55–1.43)0.61
      Platelet count0.85 (0.55–1.32)0.47
      low asterisk HRs correspond to an SD increase in the predictor variable.
      Table 3Comparison of Red cell distribution width, blood urea nitrogen, and N-terminal–pro–B-type natriuretic peptide as predictors of mortality
      ModelHR (95% CI)
      Per SD increase in RDW.
      p Value
      Per SD increase in RDW.
      LR Test p Value
      Model 1: RDW (univariate)1.63 (1.16–2.30)0.005
      Model 2: RDW + log NT–pro-BNP1.63 (1.15–2.31)0.0060.071
      Model 2 versus model 1.
      Model 3: RDW + log BUN1.46 (1.02–2.09)0.0410.037
      Model 3 versus model 1.
      Model 4: RDW + log BUN + log NT–pro-BNP1.48 (1.02–2.45)0.0370.39
      Model 4 versus model 3.
      LR = likelihood ratio.
      low asterisk Per SD increase in RDW.
      Model 2 versus model 1.
      Model 3 versus model 1.
      § Model 4 versus model 3.

      Discussion

      In a prospective study of 162 patients, we found that increased RDW was independently associated with increased mortality in PH. Our results in patients with PH and right-sided heart failure are complementary to recent data that have demonstrated the prognostic utility of RDW in chronic left-sided heart failure, in patients with coronary artery disease, and in unselected patients who undergo coronary angiography.
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      • Tonelli M.
      • Sacks F.
      • Arnold M.
      • Moye L.
      • Davis B.
      • Pfeffer M.
      Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease.

      Cavusoglu E, Chopra V, Gupta A, Battala VR, Poludasu S, Eng C, Marmur JD. Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography. Int J Cardiol. In press.

      Unlike these other studies, RDW values in our study were higher (highest tertile >19.5% vs >14.4% in the study by Cavusoglu et al

      Cavusoglu E, Chopra V, Gupta A, Battala VR, Poludasu S, Eng C, Marmur JD. Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography. Int J Cardiol. In press.

      ; mean RDW 17.8% in our study's deceased patients vs 15.2% in patients with heart failure hospitalization or death in the study by Felker et al
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      ), suggesting that RDW in patients with hemodynamically significant PH is higher than in those without PH. The survival curves shown in Figure 2 overlap in the first year and then diverge, the cause of which is unknown. This phenomenon may reflect the ability of RDW to provide insight into risk for more chronic causes of death that are the culmination of multiple pathophysiologic processes (nutritional deficiencies, renal and hepatic dysfunction, and/or inflammatory stressors).
      There was no significant association between RDW tertiles and hemodynamic variables. On correlation analysis, only right atrial pressure was loosely associated with RDW, although patients in the highest RDW tertile were more often taking diuretics. Nonetheless, these data suggest that the relation between RDW and death is not simply due to hemodynamic abnormalities in patients with high RDW. Although anemia is a strong prognostic marker in heart failure syndromes,
      • Felker G.M.
      • Adams Jr, K.F.
      • Gattis W.A.
      • O'Connor C.M.
      Anemia as a risk factor and therapeutic target in heart failure.
      the association between RDW and death in our study was independent of baseline hemoglobin and mean corpuscular volume.
      We also found that RDW outperformed NT–pro-BNP as a prognostic indicator in PH, which may be due to the decreased variability of RDW values compared to NT–pro-BNP
      • Wu A.H.
      • Smith A.
      • Wieczorek S.
      • Mather J.F.
      • Duncan B.
      • White C.M.
      • McGill C.
      • Katten D.
      • Heller G.
      Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure.
      and the ability of RDW to encompass cardiovascular and noncardiovascular risk factors for death. Regardless of the reason for RDW's superiority over NT–pro-BNP as a prognostic marker, our findings suggest that using RDW (which is a routine part of the complete blood count) may be a cost-effective alternative to the newer, more expensive NT–pro-BNP.
      Increased RDW is usually associated with ineffective red cell production (e.g., iron deficiency) or hemolysis but has recently been associated with adverse outcomes in cardiovascular and noncardiovascular disease states.
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      • Tonelli M.
      • Sacks F.
      • Arnold M.
      • Moye L.
      • Davis B.
      • Pfeffer M.
      Relation between red blood cell distribution width and cardiovascular event rate in people with coronary disease.

      Cavusoglu E, Chopra V, Gupta A, Battala VR, Poludasu S, Eng C, Marmur JD. Relation between red blood cell distribution width (RDW) and all-cause mortality at two years in an unselected population referred for coronary angiography. Int J Cardiol. In press.

      • Patel K.V.
      • Ferrucci L.
      • Ershler W.B.
      • Longo D.L.
      • Guralnik J.M.
      Red blood cell distribution width and the risk of death in middle-aged and older adults.
      • Perlstein T.S.
      • Weuve J.
      • Pfeffer M.A.
      • Beckman J.A.
      Red blood cell distribution width and mortality risk in a community-based prospective cohort.
      The mechanisms underlying the association between RDW and adverse outcomes in heart failure, including right-sided heart failure and PH, are unknown. RDW may serve as an integrative measure of multiple processes simultaneously occurring in chronic heart failure, such as kidney dysfunction, hepatic congestion, and nutritional deficiencies.
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      Others have speculated that elevated RDW may simply reflect an underlying inflammatory state that is associated with adverse outcomes.
      • Felker G.M.
      • Allen L.A.
      • Pocock S.J.
      • Shaw L.K.
      • McMurray J.J.
      • Pfeffer M.A.
      • Swedberg K.
      • Wang D.
      • Yusuf S.
      • Michelson E.L.
      • Granger C.B.
      Red cell distribution width as a novel prognostic marker in heart failure: data from the CHARM Program and the Duke Databank.
      • Ridker P.M.
      • Rifai N.
      • Clearfield M.
      • Downs J.R.
      • Weis S.E.
      • Miles J.S.
      • Gotto Jr, A.M.
      Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.
      • Sesso H.D.
      • Buring J.E.
      • Rifai N.
      • Blake G.J.
      • Gaziano J.M.
      • Ridker P.M.
      C-reactive protein and the risk of developing hypertension.
      For example, RDW may be related to inflammatory cytokines, known prognostic markers in chronic heart failure. Cytokines appear to play a role in heart failure prognosis and may also affect iron metabolism and bone marrow function.
      • Chiari M.M.
      • Bagnoli R.
      • De Luca P.D.
      • Monti M.
      • Rampoldi E.
      • Cunietti E.
      Influence of acute inflammation on iron and nutritional status indexes in older inpatients.
      • Pierce C.N.
      • Larson D.F.
      Inflammatory cytokine inhibition of erythropoiesis in patients implanted with a mechanical circulatory assist device.
      In our study, the prevalence of connective tissue disease increased with increasing tertiles of RDW, which adds support to the hypothesis that RDW is a marker of underlying inflammation.
      Limitations of our study include a study sample composed of patients cared for by a single tertiary referral practice, a small sample size, and a limited number of deaths. Additional limitations include the lack of systematic evaluation of right ventricular function by echocardiography (which may have provided additional insight into the relation between RDW and death) and the lack of data on lung function. However, oxygen use and arterial oxygen saturation did not differ by tertile of RDW. Although we determined the causes of death in all deceased patients, there were not enough outcomes available to determine whether elevated RDW was associated with specific causes of death. Finally, we did not investigate the causes of elevated RDW, such as iron deficiency or hemolysis, which is necessary to better understand the relation between RDW and death. Future studies may also benefit from examining the association between RDW and inflammatory markers, such as high-sensitivity C-reactive protein, to better understand the relations among RDW, inflammation, and adverse outcomes in PH.

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