Clinica Chimica Acta 446 (2015) 272–276
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Red blood cell distribution width predicts responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension Qunying Xi a,b, Zhihong Liu b,⁎, Zhihui Zhao b, Qin Luo b a
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China Center for Pulmonary Vascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China
b
a r t i c l e
i n f o
Article history: Received 27 September 2014 Received in revised form 18 April 2015 Accepted 28 April 2015 Available online 9 May 2015 Keywords: Pulmonary hypertension Acute pulmonary vasodilator testing Red blood cell distribution width
a b s t r a c t Background: Red blood cell distribution width (RDW) has been shown to predict clinical outcomes in cardiopulmonary vascular diseases. We investigated whether RDW is useful to predict responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods: RDW was determined in 167 IPAH patients who underwent acute pulmonary vasodilator testing. All subjects were followed up for 20 ± 10 months. Results: Nineteen out of 167 patients (11.4%) were acute pulmonary vasodilator testing responders. Patients with lower RDW levels ≤13.65% (sensitivity 89.5%, specificity 52.7%; AUC: 0.747, 95% CI: 0.632 to 0.861) were more likely to have a positive response. Multivariate logistic regression analysis showed that RDW ≤ 13.65% independently predicted responsiveness of vasodilator testing in patients with IPAH (OR 18.453, 95% CI 2.279– 149.391, p = 0.006). RDW correlated with disease severity evaluated by clinical parameters. Patients with increased RDW (N13.65%) had significantly increased risk of all-cause death (Log-rank p = 0.007). Conclusions: RDW independently predicts responsiveness of acute pulmonary vasodilator testing in patients with IPAH. RDW is associated with disease severity and all-cause death. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Treatment of pulmonary arterial hypertension (PAH) is challenging, though several PAH-specific therapies have been implemented since the last decade. Pulmonary vasodilator testing is helpful for the selection of appropriate medical therapy for patients with idiopathic pulmonary arterial hypertension (IPAH). Only the positive responders can probably benefit from long-term use of calcium channel blocker. While for those non-responders, calcium channel blocker therapy might lead to deleterious reactions, such as systemic hypotension, aggravated heart failure and death. Some biomarkers and clinical risk models have been established for prognosis of PAH. However, no
predictor for responsiveness in acute pulmonary vasodilator testing has been explored so far. Red blood cell distribution width (RDW), an index of heterogeneity of erythrocytes, has been typically used to differentiate the causes of anemia. Recently, evidence derived from a variety of clinical studies has demonstrated that RDW is a powerful predictor for prognosis of many cardiopulmonary vascular disorders, such as coronary artery disease [1], chronic heart failure [2], pulmonary thromboembolism [3], and pulmonary hypertension [4,5]. The prediction role of RDW in responsiveness in pulmonary vasodilator testing has never been explored before. Thus, in the present study we investigated the predictive role of RDW in vasodilator reactions in patients with IPAH. 2. Materials and methods
Abbreviations: PAH, pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; RDW, red blood cell distribution width; mPAP, mean pulmonary artery pressure; RHC, right heart catheterization; RVED, right ventricular end-diastolic diameter; LVED, left ventricular end-diastolic diameter; VE, minute ventilation; VCO2, CO2 production; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure. ⁎ Corresponding author at: Center for Pulmonary Vascular Diseases, Fuwai Hospital and Cardiovascular Institute, 167 Beilishi Road, Beijing 100037, China. Tel./fax: + 86 10 88396589. E-mail address: [email protected] (Z. Liu).
http://dx.doi.org/10.1016/j.cca.2015.04.041 0009-8981/© 2015 Elsevier B.V. All rights reserved.
2.1. Study population From July 2010 to January 2014, 176 consecutive adult patients with IPAH were admitted to the Center for Pulmonary Vascular Disease of Fuwai Hospital, a tertiary teaching hospital in China. Pulmonary hypertension was defined as an increase in mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest as assessed by right heart catheterization (RHC). Diagnosis of IPAH was according to diagnostic algorithm of the
Q. Xi et al. / Clinica Chimica Acta 446 (2015) 272–276
2009 guidelines for the diagnosis and treatment of pulmonary hypertension developed by the European Society of Cardiology and the European Respiratory Society [6]. Other causes of PAH were excluded on the basis of clinical characteristics, laboratory studies, echocardiography, high-resolution computed tomography, ventilation/perfusion lung scan, RHC, computed tomographic pulmonary angiography, and/ or pulmonary angiography. Exclusion criteria were (1) patients without acute pulmonary vasodilator testing results and (2) recent blood transfusion history (within 3 months). Finally, 167 patients were enrolled in this study. Data collection included clinical information, echocardiographic parameters, cardiopulmonary exercise testing results, RHC hemodynamic findings, laboratory data, and clinical outcomes. The follow-up schedule for the present study was a clinic visit every 6 months. And the patients were instructed to contact the study group if they noted any exacerbated symptoms or signs. The patients who had not made clinical visit on schedule were contacted by telephone and/or mail. The study was approved by the Human Ethics Committee of Fuwai Hospital and conformed to the Declaration of Helsinki. Written informed consent was obtained from all subjects. 2.2. Hemodynamic measurements and acute pulmonary vasodilator testing Acute pulmonary vasodilator testing was performed by using aerosolized short-acting vasodilator iloprost at the time of diagnostic RHC according to the method reported previously [7,8]. Briefly, Pulmonary capillary wedge pressure (PCWP) was measured by using a Swan– Ganz catheter (Edwards Lifesciences World Trade Co. Ltd.) Right atrial pressure and pulmonary artery pressure were recorded. Cardiac output was measured by Fick's method because of tricuspid regurgitation. Pulmonary vascular resistance (PVR) was calculated as (mPAP − PCWP) divided by cardiac output. The cardiac index (CI) was calculated by dividing cardiac output by body surface area. After baseline hemodynamic parameters had been recorded, 20 μg iloprost (Bayer-Schering Pharma) was delivered by a PARI LC STAR nebulizer (PARI GmbH) driven by a PARI TurboBOY-N compressor (PARI GmbH) for ~15 min. Another set of hemodynamic measurements and blood gases was obtained at the end of inhalation. A positive acute response was defined as a reduction of mPAP ≥10 mm Hg to reach an absolute value of mPAP ≤40 mm Hg with an increased or unchanged cardiac output. 2.3. Cardiopulmonary exercise testing Symptom-limited CPET was performed on all subjects using cycle ergometer ramping protocols by the same examiner, and the examiner was blinded to clinical data. CPET was carried out prior to RHC. Three minutes of rest was followed by 3 min of unloaded pedaling, and progressively increasing work by 5 to 20 W/min in a ramp pattern to maximum tolerance. Gas exchange variables were measured breath by breath and averaged over 10 s intervals. The equipment was calibrated in a standard procedure using reference gases prior to each test. Subjects were continuously monitored by a standard 12-lead electrocardiogram and pulse oximetry. Blood pressure was measured using a standard cuff sphygmomanometer. Peak VO2 was expressed as the highest averaged samples obtained during the test. Anaerobic threshold (AT) was determined using a combination of the V-slope method, and ventilatory equivalents for oxygen. VE and VCO2 responses throughout testing were used to calculate the VE/VCO2 slope via linear regression (y = mx + b, m = slope). 2.4. Echocardiography Standard views from the parasternal long and short axis and apical four-chamber views were used. Left ventricular ejection fraction (LVEF) was calculated by Simpson's biplane method, following manual delineation of the endocardial border in the largest (end-diastolic) and smallest (end-systolic) frames. Left ventricular end-diastolic
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diameter (LVED) and right ventricular end-diastolic diameter (RVED) were measured from 2-dimensional images in the parasternal long axis view, timed with mitral valve closure at the level of the mitral valve chordae. 2.5. Laboratory analysis Blood samples were obtained by antecubital venipuncture into ethylene diamine tetra-acetic acid-treated (for hematologic indices) or heparin-treated (for blood gas analysis) or plain tubes (for other measurements) according to hospital protocol on the day of admission or the next morning after admission. Hematologic indices including RDW were determined using the automated hematology analyzer XE-2100 (Sysmex, Co.). N-terminal pro-brain natriuretic peptide (NT-proBNP) was determined using enzyme immunoassay kit (Biomedica Medizinprodukte GmbH& Co KG). High sensitive C-reactive protein (hsCRP) was determined using particle enhanced immunoturbidimetry kit (Orion Diagnostica). Blood gas analysis was performed using a blood gas analyzer (Nova Biomedical). The other biochemical measurements were performed using a molecular analyzer (Beckman Coulter, Inc.). The investigators responsible for the measurements were unaware of the patients' baseline information. The normal reference range for RDW in the laboratory of our hospital is between 10% and 15%. 2.6. Statistical analysis Continuous variables were expressed as mean ± standard deviation and categorical variables as numbers and percentages. The receiveroperating characteristic (ROC) curve analysis was used to assess the predictive value for positive response in acute pulmonary vasodilator testing. Patients with IPAH were divided according to the RDW cut-off value obtained from ROC curve (group 1: RDW ≤ 13.65%; group 2: RDW N 13.65%). Comparisons between 2 groups of subjects were made using chi-square tests or Fisher's exact tests for categorical variables, independent-samples student's t tests for normally continuous variables, and Mann–Whitney U tests when the distribution was skewed. Correlations were evaluated via either Pearson's or Spearman's correlation tests. We then used univariate and multivariate logistic regression models to determine the independent predictors for responsiveness during vasodilator testing. Variables with p b 0.1 under univariate analysis were entered into multivariate logistic regression model. The possible confounders including age, gender, body mass index, hemoglobin, MCV were also included in the multivariate model. Kaplan–Meier cumulative survival curves were used to display survival in the 2 groups with Log-rank test. p values are 2-sided, and p b 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Science (SPSS) ver. 16.0. 3. Results 3.2. Baseline demographics and clinical characteristics One hundred and seventy-six consecutive adult patients with IPAH were screened for this study. Nine patients were excluded because they lack of acute pulmonary vasodilator testing results. Finally, 167 IPAH patients were enrolled in this study. Of the 167 subjects, 121 (72.5%) patients were women, and the mean age of the population was 33 ± 11 years. RDW ranged from 11.80% to 23.60%, with a mean value of 14.16% and standard deviation of 1.91%. Nineteen patients (11.4%) were acute pulmonary vasodilator testing responders. ROC analysis of RDW is shown in Fig. 1. According to the ROC analysis, the optimal cutoff value of RDW for predicting positive response in acute pulmonary vasodilator testing was ≤13.65% (sensitivity 89.5%, specificity 52.7%; area under the curve 0.747, 95% confidence interval (CI) 0.632 to 0.861). The baseline characteristics of two groups of IPAH patients clarified by cutoff RDW value were displayed in Table 1. Patients with
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Q. Xi et al. / Clinica Chimica Acta 446 (2015) 272–276 Table 1 Baseline characteristics of study patients. Variable
RDW ≤13.65% (n = 87)
RDW N13.65% (n = 80)
p value
Age (years) Female gender Body mass index (kg/m2) Co-morbidities Systemic hypertension Diabetes mellitus Coronary artery disease Hyperlipidemia WHO functional class I–II III–IV Medications Diuretics Digoxin Calcium channel blockers Warfarin Specific drug therapy Prostacyclins Endothelin receptor antagonists Phosphodiesterase type-5 inhibitors Combination Laboratory tests Hemoglobin (g/l) Hematocrit (%) Mean corpuscular volume (μm3) White blood cell count (109/l) Platelet (1012/l)
33 ± 11 65 (75%) 21.8 ± 3.0
33 ± 11 56 (70%) 23.5 ± 3.4
NS NS 0.001
1 0 0 4
1 2 0 1
NS NS – NS 0.001
55 (63%) 32 (37%)
30 (38%) 50 (62%)
83 (95%) 66 (76%) 22 (25%) 74 (85%)
80 (100%) 74 (93%) 10 (13%) 56 (70%)
3 (3%) 14 (16%) 42 (54%) 3 (3%)
5 (6%) 15 (19%) 45 (56%) 4 (5%)
154 ± 18 46.1 ± 4.9 90.4 ± 3.6 6.9 ± 1.8 186.2 ±
146 ± 26 44.9 ± 6.9 86.6 ± 8.2 6.8 ± 1.9 183.3 ±
0.029 NS b0.001 NS NS
54.9 66.2 ± 14.8 140.3 ± 2.2 1096 ± 642 3.31 ± 3.84 95.9 ± 2.2
63.5 69.9 ± 14.3 140.9 ± 2.7 1692 ± 1048 3.65 ± 3.87 95.4 ± 2.6
NS NS b0.001 NS NS
37.3 ± 5.4 64.9 ± 6.0 29.9 ± 5.9 0.83 ± 0.25
36.1 ± 5.5 64.4 ± 6.6 34.2 ± 6.8 0.98 ± 0.27
NS NS b0.001 b0.001
13.4 ± 3.6 38.9 ± 9.9
12.0 ± 3.1 46.3 ± 15.6
0.021 0.002
5±4 59 ± 18 2.9 ± 0.9 13.8 ± 6.1 7±3 17 (20%)
6±5 61 ± 18 2.5 ± 0.9 16.6 ± 8.8 9±3 2 (3%)
NS NS 0.008 0.021 0.015 b0.001
Fig. 1. Receive-operating characteristic curve for RDW.
higher RDW values (N13.65%) had higher body mass index (BMI) and poorer World Health Organization (WHO) functional class. They were more likely to have use of digoxin. While patients with lower RDW values were more likely to have use of calcium channel blockers and warfarin. Levels of NT-proBNP were significantly decreased in patients with lower RDW. Patients with lower RDW had less RVED, less RVED/ LVED, better performance in cardiopulmonary exercise testing, and better hemodynamic parameters during RHC. 3.3. RDW independently predicts responsiveness in acute pulmonary vasodilator testing Results of the univariate and multivariate logistic regression analyses for responsiveness of acute pulmonary vasodilator testing are listed in Table 2. In univariate analysis, WHO functional class I–II, RDW ≤ 13.65%, mPAP, PVR, RVED, and the ratio of RVED/LVED were found to have prognostic power for responsiveness. While in multivariate logistic regression models which adjusted for age, BMI, gender, hemoglobin, MCV, WHO functional class, PCWP, RVED, and RVED/ LVED, only RDW ≤ 13.65% and mPAP were independently associated with responsiveness of vasodilator testing in patients with IPAH. 3.4. RDW associated with disease severity in patients with IPAH Positive correlations were observed between RDW and WHO function class (rs = 0.236, p = 0.002), NT-proBNP (rs = 0.334, p b 0.001), RVED (rs = 0.268, p = 0.001), REVD/LVED (rs = 0.241, p = 0.002), VE/VCO2 slope (rs = 0.352, p b 0.001), mean right atrial pressure (rs = 0.173, p = 0.026), along with negative correlations were observed between RDW and peak O2 consumption (rs = −0.352, p b 0.001), and cardiac index (rs = − 0.186, p = 0.016). However, there was no correlation between RDW and mPAP (rs = 0.046, p = NS), and PVR (rs = 0.114, p = NS). In PVR (9.93 ± 2.37 vs. 9.11 ± 4.11 Wood units, p = NS), mPAP (47.3 ± 5.1 vs. 47.6 ± 10.9 mm Hg, p = NS) and age (37 ± 12 vs. 32 ± 10 y, p = NS)-matched 2 groups (responders vs. non-responders, n = 19 respectively), RDW (12.86% ± 0.75% vs.
Creatinine (mmol/l) Sodium (mmol/l) NT-proBNP (ng/l) hsCRP (mg/l) Oxygen saturation (%) Echocardiographic measurements LVED (mm) LVEF (%) RVED (mm) RVED/LVED Cardiopulmonary exercise testing Peak O2 consumption (ml/min/kg) VE/VCO2 slope (l/min/l/min) Hemodynamics Mean right atrial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Cardiac index (l/min/m2) Pulmonary vascular resistance (wood units) Pulmonary capillary wedge pressure (mm Hg) Positive responder in acute vasodilator testing
NS 0.004 0.048 0.025 NS
Data are presented as mean ± standard deviation or number of patients (%). LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; RVED: right ventricular end-diastolic diameter; VE: minute ventilation; VCO2: CO2 production.
14.51% ± 2.24%, p = 0.006) was significantly lower in responders, though there was no difference of hemoglobin and MCV between the 2 groups (Fig. 2). 3.5. Elevated RDW values associated with increased risk of all-cause death Ten out of 157 patients (6.4%) died during a mean follow-up period of 20 ± 10 months. Ten patients lost follow-up. According to Kaplan– Meier survival analysis, a significant difference was found between the 2 groups (patients with RDW N13.65% and patients with RDW ≤13.65%) in terms of survival rate (Log-rank p = 0.007) (Fig. 3). 4. Discussion In the present study, we examined the role of RDW in predicting responsiveness in acute pulmonary vasodilator testing in 167 patients
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Table 2 Univariate and multivariate analyses for pulmonary vasodilator testing. Variable
WHO functional class I–II Hemoglobin Creatinine MCV RDW ≤13.65% NT-proBNP hsCRP VE/VCO2 slope hsCRP Peak O2 consumption Mean right atrial pressure mPAP PCWP PVR Cardiac index RVED RVED/LVED
Univariate analysis
Multivariate analysis
OR
(95% CI)
p value
4.179 4.179 0.993 0.995 1.048 9.471 0.999 1.075 0.948 1.063 0.971 0.929 0.857 0.838 1.384 0.885 0.022
(1.324–14.480) (1.324–14.480) (0.973–1.014) (0.963–1.029) (0.967–1.136) (2.113–42.460) (0.999–1.000) (0.944–1.223) (0.890–1.010) (0.910–1.240) (0.860–1.097) (0.887–0.972) (0.736–0.998) (0.750–0.936) (0.898–2.133) (0.807–0.971) (0.002–0.290)
0.015 0.015 NS NS NS 0.003 NS NS NS NS NS 0.002 0.047 0.002 NS 0.010 0.004
OR
(95% CI)
p value
18.453
(2.279–149.391)
0.006
WHO: World Health Organization; VE: minute ventilation; VCO2: CO2 production; mPAP: mean pulmonary arterial pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RVED: right ventricular end-diastolic diameter; LVED: left ventricular end-diastolic diameter.
with IPAH. The key findings are as following: 1) RDW was an independent and potent predictor for responsiveness, lower RDW value was associated with a positive response, and 2) RDW levels were associated with disease severity and all-cause death in patients with IPAH. Our study showed that mPAP was an independent determinant of responsiveness. Lower mPAP was more likely led to a positive response. The result is in line with previous observations that a positive pulmonary vasodilator test is more common in patients with less severe hemodynamic profiles [8,9]. However, the most interesting thing is that RDW predicts responsiveness independently of mPAP and PVR. There is no correlation between RDW and mPAP, nor RDW and PVR. RDW differed significantly between mPAP and PVR-matched responders and non-responders. These findings suggest that the predictive role of RDW in acute pulmonary vasodilator testing is based on other mechanisms rather than hemodynamic characteristics. Acute pulmonary vasodilator testing is helpful in selection of the appropriate medical therapy for IPAH. Positive tests were observed in about 10–15% of IPAH patients [10]. The frequency of positive test in the present study is 11.4%. The results accord with previous reports. More than half of the positive responders could benefit from long-term therapy of calcium channel blocker. And a positive response to pulmonary vasodilator testing is considered to predict a better
survival [9]. It's well known that acute pulmonary vasodilator testing establishes the relative contribution of reversible vasoconstriction compared with fixed stenosis in patients with PAH. However, this perception is debatable. It could not explain why only a minority of IPAH patients display positive response to vasodilator testing, while others who are also within the early stages (favorable WHO function class, same levels of PVR and mPAP obtained from RHC) remain negative response. And in a recent study [11], investigators performed RHC and intravascular ultrasound simultaneously in 19 patients with IPAH. They found out that the patients with a positive vasodilator testing do not necessarily have a real vasodilatation on intravascular ultrasound. It means that a positive response to vasodilator testing could not be simply interpreted as the relative contribution of reversible vasoconstriction. In other words, the positive response might be determined by other mechanisms in some patients. Our present study has shown that RDW correlate with responsiveness of acute vasodilator testing. IPAH patients with lower RDW values are more likely to be positive responders. It might provide an important clue to explore the determinants of responsiveness in vasodilator testing. RDW is an inexpensive, readily available parameter in routine complete blood cell count test. It is an index of anisocytosis and has been generally used to aid in the differentiation of anemia. A series of recent
Fig. 2. In PVR, mPAP, and age-matched 2 groups (responders vs. non-responders, n = 19 respectively), RDW was significantly lower in responders, though there was no difference of hemoglobin and MCV between the two groups.
Fig. 3. Kaplan–Meier survival curves for IPAH patients clarified by RDW cutoff value.
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studies found out that RDW played an important role in predicting of prognosis of many cardiopulmonary vascular diseases including coronary artery disease [1], heart failure [2], and PAH [4,5,12]. Our study provides new evidence that RDW is not only an important predictor of prognosis of PAH, but also an independent and potent predictor of responsiveness in acute pulmonary vasodilator testing. A recent study showed that right heart function evaluated by echocardiography is better in responders than in non-responders among patients with PAH [13]. And in the present study, we found that RDW was associated with disease severity evaluated by WHO functional class, NT-proBNP, REVD, peak O2 consumption, and cardiac index obtained during RHC. Thus, we assume that the mechanism underlying the linkage between RDW and acute pulmonary vasodilator testing is probably linked with the difference of heart function in responders and non-responders. Several mechanisms have been proposed to explain the association between RDW and prognosis of cardiopulmonary vascular disease. Malnutrition, including iron deficiency has been suggested to be an important linkage between RDW levels and prognosis of heart failure [14,15], and PAH [16,17]. Inflammation [18,19] and oxidative stress [20,21] have been suggested to be other important determinants of RDW. We determined levels of hsCRP, an indicator for inflammation, in the present population. However, there was no correlation between RDW and hsCRP. The results are different from a previous retrospective study [19], which reported a significant association of RDW with hsCRP in a cohort of unselected adult outpatients. Different study population might could explain the disparity. Unfortunately, we hadn't assessed the iron metabolism and levels of oxidative stress and other inflammation markers in the present study. Limitation of our study includes the lack of systematic evaluation of iron metabolism and inflammation, oxidative stress states, so that to explore the underlying mechanism for the predictive role of RDW. Other limitations include a small sample size by a single tertiary teaching hospital, we could not rule out the residual confounding and bias although we did statistical adjustment as possible. In conclusion, we found that RDW was an independent and potent predictor for responsiveness, lower RDW value was associated with a positive response. And RDW levels associated with disease severity and all-cause death in patients with IPAH. Acknowledgment The authors acknowledge the staff members of the ward of Pulmonary Vascular Disease at Fuwai Hospital for their assistance in data collection. References [1] Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol 2010;105:312–7.
[2] Borne Y, Smith JG, Melander O, Hedblad B, Engstrom G. Red cell distribution width and risk for first hospitalization due to heart failure: a population-based cohort study. Eur J Heart Fail 2011;13:1355–61. [3] Zorlu A, Bektasoglu G, Guven FM, et al. Usefulness of admission red cell distribution width as a predictor of early mortality in patients with acute pulmonary embolism. Am J Cardiol 2012;109:128–34. [4] Hampole CV, Mehrotra AK, Thenappan T, Gomberg-Maitland M, Shah SJ. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. Am J Cardiol 2009;104:868–72. [5] Rhodes CJ, Wharton J, Howard LS, Gibbs JS, Wilkins MR. Red cell distribution width outperforms other potential circulating biomarkers in predicting survival in idiopathic pulmonary arterial hypertension. Heart 2011;97:1054–60. [6] Galie N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. [7] Jing ZC, Jiang X, Han ZY, et al. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension. Eur Respir J 2009;33:1354–60. [8] Zhang HL, Liu ZH, Wang Y, et al. Acute responses to inhalation of Iloprost in patients with pulmonary hypertension. Chin Med J (Engl) 2012;125:2826–31. [9] Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–11. [10] Tonelli AR, Alnuaimat H, Mubarak K. Pulmonary vasodilator testing and use of calcium channel blockers in pulmonary arterial hypertension. Respir Med 2010; 104:481–96. [11] Grignola JC, Domingo E, Aguilar R, et al. Acute absolute vasodilatation is associated with a lower vascular wall stiffness in pulmonary arterial hypertension. Int J Cardiol 2013;164:227–31. [12] Foris V, Kovacs G, Tscherner M, Olschewski A, Olschewski H. Biomarkers in pulmonary hypertension: what do we know? Chest 2013;144:274–83. [13] Liu YT, Li MT, Fang Q, et al. Right-heart function related to the results of acute pulmonary vasodilator testing in patients with pulmonary arterial hypertension caused by connective tissue disease. J Am Soc Echocardiogr 2012;25:274–9. [14] Allen LA, Felker GM, Mehra MR, et al. Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure. J Card Fail 2010;16: 230–8. [15] Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohaszka Z, Janoskuti L. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J 2009;158:659–66. [16] Decker I, Ghosh S, Comhair SA, et al. High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertension. Clin Transl Sci 2011;4: 253–8. [17] Rhodes CJ, Howard LS, Busbridge M, et al. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 2011;58:300–9. [18] de Gonzalo-Calvo D, de Luxan-Delgado B, Rodriguez-Gonzalez S, et al. Interleukin 6, soluble tumor necrosis factor receptor I and red blood cell distribution width as biological markers of functional dependence in an elderly population: a translational approach. Cytokine 2012;58:193–8. [19] Lippi G, Targher G, Montagnana M, Salvagno GL, Zoppini G, Guidi GC. Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Arch Pathol Lab Med 2009;133:628–32. [20] Semba RD, Patel KV, Ferrucci L, et al. Serum antioxidants and inflammation predict red cell distribution width in older women: the Women's Health and Aging Study I. Clin Nutr 2010;29:600–4. [21] Grzelak A, Kruszewski M, Macierzynska E, et al. The effects of superoxide dismutase knockout on the oxidative stress parameters and survival of mouse erythrocytes. Cell Mol Biol Lett 2009;14:23–34.
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Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim
Red blood cell distribution width predicts responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension Qunying Xi a,b, Zhihong Liu b,⁎, Zhihui Zhao b, Qin Luo b a
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China Center for Pulmonary Vascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China
b
a r t i c l e
i n f o
Article history: Received 27 September 2014 Received in revised form 18 April 2015 Accepted 28 April 2015 Available online 9 May 2015 Keywords: Pulmonary hypertension Acute pulmonary vasodilator testing Red blood cell distribution width
a b s t r a c t Background: Red blood cell distribution width (RDW) has been shown to predict clinical outcomes in cardiopulmonary vascular diseases. We investigated whether RDW is useful to predict responsiveness of acute pulmonary vasodilator testing in patients with idiopathic pulmonary arterial hypertension (IPAH). Methods: RDW was determined in 167 IPAH patients who underwent acute pulmonary vasodilator testing. All subjects were followed up for 20 ± 10 months. Results: Nineteen out of 167 patients (11.4%) were acute pulmonary vasodilator testing responders. Patients with lower RDW levels ≤13.65% (sensitivity 89.5%, specificity 52.7%; AUC: 0.747, 95% CI: 0.632 to 0.861) were more likely to have a positive response. Multivariate logistic regression analysis showed that RDW ≤ 13.65% independently predicted responsiveness of vasodilator testing in patients with IPAH (OR 18.453, 95% CI 2.279– 149.391, p = 0.006). RDW correlated with disease severity evaluated by clinical parameters. Patients with increased RDW (N13.65%) had significantly increased risk of all-cause death (Log-rank p = 0.007). Conclusions: RDW independently predicts responsiveness of acute pulmonary vasodilator testing in patients with IPAH. RDW is associated with disease severity and all-cause death. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Treatment of pulmonary arterial hypertension (PAH) is challenging, though several PAH-specific therapies have been implemented since the last decade. Pulmonary vasodilator testing is helpful for the selection of appropriate medical therapy for patients with idiopathic pulmonary arterial hypertension (IPAH). Only the positive responders can probably benefit from long-term use of calcium channel blocker. While for those non-responders, calcium channel blocker therapy might lead to deleterious reactions, such as systemic hypotension, aggravated heart failure and death. Some biomarkers and clinical risk models have been established for prognosis of PAH. However, no
predictor for responsiveness in acute pulmonary vasodilator testing has been explored so far. Red blood cell distribution width (RDW), an index of heterogeneity of erythrocytes, has been typically used to differentiate the causes of anemia. Recently, evidence derived from a variety of clinical studies has demonstrated that RDW is a powerful predictor for prognosis of many cardiopulmonary vascular disorders, such as coronary artery disease [1], chronic heart failure [2], pulmonary thromboembolism [3], and pulmonary hypertension [4,5]. The prediction role of RDW in responsiveness in pulmonary vasodilator testing has never been explored before. Thus, in the present study we investigated the predictive role of RDW in vasodilator reactions in patients with IPAH. 2. Materials and methods
Abbreviations: PAH, pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; RDW, red blood cell distribution width; mPAP, mean pulmonary artery pressure; RHC, right heart catheterization; RVED, right ventricular end-diastolic diameter; LVED, left ventricular end-diastolic diameter; VE, minute ventilation; VCO2, CO2 production; PVR, pulmonary vascular resistance; PCWP, pulmonary capillary wedge pressure. ⁎ Corresponding author at: Center for Pulmonary Vascular Diseases, Fuwai Hospital and Cardiovascular Institute, 167 Beilishi Road, Beijing 100037, China. Tel./fax: + 86 10 88396589. E-mail address: [email protected] (Z. Liu).
http://dx.doi.org/10.1016/j.cca.2015.04.041 0009-8981/© 2015 Elsevier B.V. All rights reserved.
2.1. Study population From July 2010 to January 2014, 176 consecutive adult patients with IPAH were admitted to the Center for Pulmonary Vascular Disease of Fuwai Hospital, a tertiary teaching hospital in China. Pulmonary hypertension was defined as an increase in mean pulmonary artery pressure (mPAP) ≥25 mm Hg at rest as assessed by right heart catheterization (RHC). Diagnosis of IPAH was according to diagnostic algorithm of the
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2009 guidelines for the diagnosis and treatment of pulmonary hypertension developed by the European Society of Cardiology and the European Respiratory Society [6]. Other causes of PAH were excluded on the basis of clinical characteristics, laboratory studies, echocardiography, high-resolution computed tomography, ventilation/perfusion lung scan, RHC, computed tomographic pulmonary angiography, and/ or pulmonary angiography. Exclusion criteria were (1) patients without acute pulmonary vasodilator testing results and (2) recent blood transfusion history (within 3 months). Finally, 167 patients were enrolled in this study. Data collection included clinical information, echocardiographic parameters, cardiopulmonary exercise testing results, RHC hemodynamic findings, laboratory data, and clinical outcomes. The follow-up schedule for the present study was a clinic visit every 6 months. And the patients were instructed to contact the study group if they noted any exacerbated symptoms or signs. The patients who had not made clinical visit on schedule were contacted by telephone and/or mail. The study was approved by the Human Ethics Committee of Fuwai Hospital and conformed to the Declaration of Helsinki. Written informed consent was obtained from all subjects. 2.2. Hemodynamic measurements and acute pulmonary vasodilator testing Acute pulmonary vasodilator testing was performed by using aerosolized short-acting vasodilator iloprost at the time of diagnostic RHC according to the method reported previously [7,8]. Briefly, Pulmonary capillary wedge pressure (PCWP) was measured by using a Swan– Ganz catheter (Edwards Lifesciences World Trade Co. Ltd.) Right atrial pressure and pulmonary artery pressure were recorded. Cardiac output was measured by Fick's method because of tricuspid regurgitation. Pulmonary vascular resistance (PVR) was calculated as (mPAP − PCWP) divided by cardiac output. The cardiac index (CI) was calculated by dividing cardiac output by body surface area. After baseline hemodynamic parameters had been recorded, 20 μg iloprost (Bayer-Schering Pharma) was delivered by a PARI LC STAR nebulizer (PARI GmbH) driven by a PARI TurboBOY-N compressor (PARI GmbH) for ~15 min. Another set of hemodynamic measurements and blood gases was obtained at the end of inhalation. A positive acute response was defined as a reduction of mPAP ≥10 mm Hg to reach an absolute value of mPAP ≤40 mm Hg with an increased or unchanged cardiac output. 2.3. Cardiopulmonary exercise testing Symptom-limited CPET was performed on all subjects using cycle ergometer ramping protocols by the same examiner, and the examiner was blinded to clinical data. CPET was carried out prior to RHC. Three minutes of rest was followed by 3 min of unloaded pedaling, and progressively increasing work by 5 to 20 W/min in a ramp pattern to maximum tolerance. Gas exchange variables were measured breath by breath and averaged over 10 s intervals. The equipment was calibrated in a standard procedure using reference gases prior to each test. Subjects were continuously monitored by a standard 12-lead electrocardiogram and pulse oximetry. Blood pressure was measured using a standard cuff sphygmomanometer. Peak VO2 was expressed as the highest averaged samples obtained during the test. Anaerobic threshold (AT) was determined using a combination of the V-slope method, and ventilatory equivalents for oxygen. VE and VCO2 responses throughout testing were used to calculate the VE/VCO2 slope via linear regression (y = mx + b, m = slope). 2.4. Echocardiography Standard views from the parasternal long and short axis and apical four-chamber views were used. Left ventricular ejection fraction (LVEF) was calculated by Simpson's biplane method, following manual delineation of the endocardial border in the largest (end-diastolic) and smallest (end-systolic) frames. Left ventricular end-diastolic
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diameter (LVED) and right ventricular end-diastolic diameter (RVED) were measured from 2-dimensional images in the parasternal long axis view, timed with mitral valve closure at the level of the mitral valve chordae. 2.5. Laboratory analysis Blood samples were obtained by antecubital venipuncture into ethylene diamine tetra-acetic acid-treated (for hematologic indices) or heparin-treated (for blood gas analysis) or plain tubes (for other measurements) according to hospital protocol on the day of admission or the next morning after admission. Hematologic indices including RDW were determined using the automated hematology analyzer XE-2100 (Sysmex, Co.). N-terminal pro-brain natriuretic peptide (NT-proBNP) was determined using enzyme immunoassay kit (Biomedica Medizinprodukte GmbH& Co KG). High sensitive C-reactive protein (hsCRP) was determined using particle enhanced immunoturbidimetry kit (Orion Diagnostica). Blood gas analysis was performed using a blood gas analyzer (Nova Biomedical). The other biochemical measurements were performed using a molecular analyzer (Beckman Coulter, Inc.). The investigators responsible for the measurements were unaware of the patients' baseline information. The normal reference range for RDW in the laboratory of our hospital is between 10% and 15%. 2.6. Statistical analysis Continuous variables were expressed as mean ± standard deviation and categorical variables as numbers and percentages. The receiveroperating characteristic (ROC) curve analysis was used to assess the predictive value for positive response in acute pulmonary vasodilator testing. Patients with IPAH were divided according to the RDW cut-off value obtained from ROC curve (group 1: RDW ≤ 13.65%; group 2: RDW N 13.65%). Comparisons between 2 groups of subjects were made using chi-square tests or Fisher's exact tests for categorical variables, independent-samples student's t tests for normally continuous variables, and Mann–Whitney U tests when the distribution was skewed. Correlations were evaluated via either Pearson's or Spearman's correlation tests. We then used univariate and multivariate logistic regression models to determine the independent predictors for responsiveness during vasodilator testing. Variables with p b 0.1 under univariate analysis were entered into multivariate logistic regression model. The possible confounders including age, gender, body mass index, hemoglobin, MCV were also included in the multivariate model. Kaplan–Meier cumulative survival curves were used to display survival in the 2 groups with Log-rank test. p values are 2-sided, and p b 0.05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Science (SPSS) ver. 16.0. 3. Results 3.2. Baseline demographics and clinical characteristics One hundred and seventy-six consecutive adult patients with IPAH were screened for this study. Nine patients were excluded because they lack of acute pulmonary vasodilator testing results. Finally, 167 IPAH patients were enrolled in this study. Of the 167 subjects, 121 (72.5%) patients were women, and the mean age of the population was 33 ± 11 years. RDW ranged from 11.80% to 23.60%, with a mean value of 14.16% and standard deviation of 1.91%. Nineteen patients (11.4%) were acute pulmonary vasodilator testing responders. ROC analysis of RDW is shown in Fig. 1. According to the ROC analysis, the optimal cutoff value of RDW for predicting positive response in acute pulmonary vasodilator testing was ≤13.65% (sensitivity 89.5%, specificity 52.7%; area under the curve 0.747, 95% confidence interval (CI) 0.632 to 0.861). The baseline characteristics of two groups of IPAH patients clarified by cutoff RDW value were displayed in Table 1. Patients with
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Q. Xi et al. / Clinica Chimica Acta 446 (2015) 272–276 Table 1 Baseline characteristics of study patients. Variable
RDW ≤13.65% (n = 87)
RDW N13.65% (n = 80)
p value
Age (years) Female gender Body mass index (kg/m2) Co-morbidities Systemic hypertension Diabetes mellitus Coronary artery disease Hyperlipidemia WHO functional class I–II III–IV Medications Diuretics Digoxin Calcium channel blockers Warfarin Specific drug therapy Prostacyclins Endothelin receptor antagonists Phosphodiesterase type-5 inhibitors Combination Laboratory tests Hemoglobin (g/l) Hematocrit (%) Mean corpuscular volume (μm3) White blood cell count (109/l) Platelet (1012/l)
33 ± 11 65 (75%) 21.8 ± 3.0
33 ± 11 56 (70%) 23.5 ± 3.4
NS NS 0.001
1 0 0 4
1 2 0 1
NS NS – NS 0.001
55 (63%) 32 (37%)
30 (38%) 50 (62%)
83 (95%) 66 (76%) 22 (25%) 74 (85%)
80 (100%) 74 (93%) 10 (13%) 56 (70%)
3 (3%) 14 (16%) 42 (54%) 3 (3%)
5 (6%) 15 (19%) 45 (56%) 4 (5%)
154 ± 18 46.1 ± 4.9 90.4 ± 3.6 6.9 ± 1.8 186.2 ±
146 ± 26 44.9 ± 6.9 86.6 ± 8.2 6.8 ± 1.9 183.3 ±
0.029 NS b0.001 NS NS
54.9 66.2 ± 14.8 140.3 ± 2.2 1096 ± 642 3.31 ± 3.84 95.9 ± 2.2
63.5 69.9 ± 14.3 140.9 ± 2.7 1692 ± 1048 3.65 ± 3.87 95.4 ± 2.6
NS NS b0.001 NS NS
37.3 ± 5.4 64.9 ± 6.0 29.9 ± 5.9 0.83 ± 0.25
36.1 ± 5.5 64.4 ± 6.6 34.2 ± 6.8 0.98 ± 0.27
NS NS b0.001 b0.001
13.4 ± 3.6 38.9 ± 9.9
12.0 ± 3.1 46.3 ± 15.6
0.021 0.002
5±4 59 ± 18 2.9 ± 0.9 13.8 ± 6.1 7±3 17 (20%)
6±5 61 ± 18 2.5 ± 0.9 16.6 ± 8.8 9±3 2 (3%)
NS NS 0.008 0.021 0.015 b0.001
Fig. 1. Receive-operating characteristic curve for RDW.
higher RDW values (N13.65%) had higher body mass index (BMI) and poorer World Health Organization (WHO) functional class. They were more likely to have use of digoxin. While patients with lower RDW values were more likely to have use of calcium channel blockers and warfarin. Levels of NT-proBNP were significantly decreased in patients with lower RDW. Patients with lower RDW had less RVED, less RVED/ LVED, better performance in cardiopulmonary exercise testing, and better hemodynamic parameters during RHC. 3.3. RDW independently predicts responsiveness in acute pulmonary vasodilator testing Results of the univariate and multivariate logistic regression analyses for responsiveness of acute pulmonary vasodilator testing are listed in Table 2. In univariate analysis, WHO functional class I–II, RDW ≤ 13.65%, mPAP, PVR, RVED, and the ratio of RVED/LVED were found to have prognostic power for responsiveness. While in multivariate logistic regression models which adjusted for age, BMI, gender, hemoglobin, MCV, WHO functional class, PCWP, RVED, and RVED/ LVED, only RDW ≤ 13.65% and mPAP were independently associated with responsiveness of vasodilator testing in patients with IPAH. 3.4. RDW associated with disease severity in patients with IPAH Positive correlations were observed between RDW and WHO function class (rs = 0.236, p = 0.002), NT-proBNP (rs = 0.334, p b 0.001), RVED (rs = 0.268, p = 0.001), REVD/LVED (rs = 0.241, p = 0.002), VE/VCO2 slope (rs = 0.352, p b 0.001), mean right atrial pressure (rs = 0.173, p = 0.026), along with negative correlations were observed between RDW and peak O2 consumption (rs = −0.352, p b 0.001), and cardiac index (rs = − 0.186, p = 0.016). However, there was no correlation between RDW and mPAP (rs = 0.046, p = NS), and PVR (rs = 0.114, p = NS). In PVR (9.93 ± 2.37 vs. 9.11 ± 4.11 Wood units, p = NS), mPAP (47.3 ± 5.1 vs. 47.6 ± 10.9 mm Hg, p = NS) and age (37 ± 12 vs. 32 ± 10 y, p = NS)-matched 2 groups (responders vs. non-responders, n = 19 respectively), RDW (12.86% ± 0.75% vs.
Creatinine (mmol/l) Sodium (mmol/l) NT-proBNP (ng/l) hsCRP (mg/l) Oxygen saturation (%) Echocardiographic measurements LVED (mm) LVEF (%) RVED (mm) RVED/LVED Cardiopulmonary exercise testing Peak O2 consumption (ml/min/kg) VE/VCO2 slope (l/min/l/min) Hemodynamics Mean right atrial pressure (mm Hg) Mean pulmonary artery pressure (mm Hg) Cardiac index (l/min/m2) Pulmonary vascular resistance (wood units) Pulmonary capillary wedge pressure (mm Hg) Positive responder in acute vasodilator testing
NS 0.004 0.048 0.025 NS
Data are presented as mean ± standard deviation or number of patients (%). LVED: left ventricular end-diastolic diameter; LVEF: left ventricular ejection fraction; RVED: right ventricular end-diastolic diameter; VE: minute ventilation; VCO2: CO2 production.
14.51% ± 2.24%, p = 0.006) was significantly lower in responders, though there was no difference of hemoglobin and MCV between the 2 groups (Fig. 2). 3.5. Elevated RDW values associated with increased risk of all-cause death Ten out of 157 patients (6.4%) died during a mean follow-up period of 20 ± 10 months. Ten patients lost follow-up. According to Kaplan– Meier survival analysis, a significant difference was found between the 2 groups (patients with RDW N13.65% and patients with RDW ≤13.65%) in terms of survival rate (Log-rank p = 0.007) (Fig. 3). 4. Discussion In the present study, we examined the role of RDW in predicting responsiveness in acute pulmonary vasodilator testing in 167 patients
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Table 2 Univariate and multivariate analyses for pulmonary vasodilator testing. Variable
WHO functional class I–II Hemoglobin Creatinine MCV RDW ≤13.65% NT-proBNP hsCRP VE/VCO2 slope hsCRP Peak O2 consumption Mean right atrial pressure mPAP PCWP PVR Cardiac index RVED RVED/LVED
Univariate analysis
Multivariate analysis
OR
(95% CI)
p value
4.179 4.179 0.993 0.995 1.048 9.471 0.999 1.075 0.948 1.063 0.971 0.929 0.857 0.838 1.384 0.885 0.022
(1.324–14.480) (1.324–14.480) (0.973–1.014) (0.963–1.029) (0.967–1.136) (2.113–42.460) (0.999–1.000) (0.944–1.223) (0.890–1.010) (0.910–1.240) (0.860–1.097) (0.887–0.972) (0.736–0.998) (0.750–0.936) (0.898–2.133) (0.807–0.971) (0.002–0.290)
0.015 0.015 NS NS NS 0.003 NS NS NS NS NS 0.002 0.047 0.002 NS 0.010 0.004
OR
(95% CI)
p value
18.453
(2.279–149.391)
0.006
WHO: World Health Organization; VE: minute ventilation; VCO2: CO2 production; mPAP: mean pulmonary arterial pressure; PCWP: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; RVED: right ventricular end-diastolic diameter; LVED: left ventricular end-diastolic diameter.
with IPAH. The key findings are as following: 1) RDW was an independent and potent predictor for responsiveness, lower RDW value was associated with a positive response, and 2) RDW levels were associated with disease severity and all-cause death in patients with IPAH. Our study showed that mPAP was an independent determinant of responsiveness. Lower mPAP was more likely led to a positive response. The result is in line with previous observations that a positive pulmonary vasodilator test is more common in patients with less severe hemodynamic profiles [8,9]. However, the most interesting thing is that RDW predicts responsiveness independently of mPAP and PVR. There is no correlation between RDW and mPAP, nor RDW and PVR. RDW differed significantly between mPAP and PVR-matched responders and non-responders. These findings suggest that the predictive role of RDW in acute pulmonary vasodilator testing is based on other mechanisms rather than hemodynamic characteristics. Acute pulmonary vasodilator testing is helpful in selection of the appropriate medical therapy for IPAH. Positive tests were observed in about 10–15% of IPAH patients [10]. The frequency of positive test in the present study is 11.4%. The results accord with previous reports. More than half of the positive responders could benefit from long-term therapy of calcium channel blocker. And a positive response to pulmonary vasodilator testing is considered to predict a better
survival [9]. It's well known that acute pulmonary vasodilator testing establishes the relative contribution of reversible vasoconstriction compared with fixed stenosis in patients with PAH. However, this perception is debatable. It could not explain why only a minority of IPAH patients display positive response to vasodilator testing, while others who are also within the early stages (favorable WHO function class, same levels of PVR and mPAP obtained from RHC) remain negative response. And in a recent study [11], investigators performed RHC and intravascular ultrasound simultaneously in 19 patients with IPAH. They found out that the patients with a positive vasodilator testing do not necessarily have a real vasodilatation on intravascular ultrasound. It means that a positive response to vasodilator testing could not be simply interpreted as the relative contribution of reversible vasoconstriction. In other words, the positive response might be determined by other mechanisms in some patients. Our present study has shown that RDW correlate with responsiveness of acute vasodilator testing. IPAH patients with lower RDW values are more likely to be positive responders. It might provide an important clue to explore the determinants of responsiveness in vasodilator testing. RDW is an inexpensive, readily available parameter in routine complete blood cell count test. It is an index of anisocytosis and has been generally used to aid in the differentiation of anemia. A series of recent
Fig. 2. In PVR, mPAP, and age-matched 2 groups (responders vs. non-responders, n = 19 respectively), RDW was significantly lower in responders, though there was no difference of hemoglobin and MCV between the two groups.
Fig. 3. Kaplan–Meier survival curves for IPAH patients clarified by RDW cutoff value.
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studies found out that RDW played an important role in predicting of prognosis of many cardiopulmonary vascular diseases including coronary artery disease [1], heart failure [2], and PAH [4,5,12]. Our study provides new evidence that RDW is not only an important predictor of prognosis of PAH, but also an independent and potent predictor of responsiveness in acute pulmonary vasodilator testing. A recent study showed that right heart function evaluated by echocardiography is better in responders than in non-responders among patients with PAH [13]. And in the present study, we found that RDW was associated with disease severity evaluated by WHO functional class, NT-proBNP, REVD, peak O2 consumption, and cardiac index obtained during RHC. Thus, we assume that the mechanism underlying the linkage between RDW and acute pulmonary vasodilator testing is probably linked with the difference of heart function in responders and non-responders. Several mechanisms have been proposed to explain the association between RDW and prognosis of cardiopulmonary vascular disease. Malnutrition, including iron deficiency has been suggested to be an important linkage between RDW levels and prognosis of heart failure [14,15], and PAH [16,17]. Inflammation [18,19] and oxidative stress [20,21] have been suggested to be other important determinants of RDW. We determined levels of hsCRP, an indicator for inflammation, in the present population. However, there was no correlation between RDW and hsCRP. The results are different from a previous retrospective study [19], which reported a significant association of RDW with hsCRP in a cohort of unselected adult outpatients. Different study population might could explain the disparity. Unfortunately, we hadn't assessed the iron metabolism and levels of oxidative stress and other inflammation markers in the present study. Limitation of our study includes the lack of systematic evaluation of iron metabolism and inflammation, oxidative stress states, so that to explore the underlying mechanism for the predictive role of RDW. Other limitations include a small sample size by a single tertiary teaching hospital, we could not rule out the residual confounding and bias although we did statistical adjustment as possible. In conclusion, we found that RDW was an independent and potent predictor for responsiveness, lower RDW value was associated with a positive response. And RDW levels associated with disease severity and all-cause death in patients with IPAH. Acknowledgment The authors acknowledge the staff members of the ward of Pulmonary Vascular Disease at Fuwai Hospital for their assistance in data collection. References [1] Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol 2010;105:312–7.
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