Elevated Red Cell Distribution Width Is Associated With Poor Clinical Outcomes In Non-ischemic Dilated Cardiomyopathy

BackgroundHeart failure is a chronic and progressive disease with high mortality overall world.It could be induced by various causes and presented as the final stage of all heart diseases.In clinical practice,ischemic cardiomyopathy and non-ischemic cardiomyopathy are two major pathogenesis of HF.And Non-Ischemic Dilated cardiomyopathy is the primary non-ischemic heart muscle disease,as well as one of the major cause for heart failure.Red blood cell distribution width is a simple parameter of the standard full blood count and a measure of heterogeneity in the size of circulating erythrocytes,which has traditionally played a role in the differential diagnosis of anaemia.It has been investigated elevated RDW was deeply related with adverse outcomes of HF patients.However,this association was dependent of other haematological variables.The etiology of heart failure is also a complex and may be caused by coronary artery disease,endocrine disease,heart valve disease,hypertension,acute pulmonary embolism,emphysema or other chronic lung diseases.NIDCM occupies relatively certain proportion of HF,and the pathogenesis and prognosis of NIDCM are completely different from those of heart failure caused by ischemia or other reasons.However,the prognostic impact of RDW in patients with NIDCM has not been fully elucidated.ObjectiveIn the present study,we investigated the association between RDW level and long-term prognosis in patients with NIDCM.Methods124 consecutive cases of inpatient with NIDCM(91 men;mean age:51.6±14.7years;range,16–80)were selected from the Department of Cardiology in the First Affiliated Hospital of Zhengzhou University.NIDCM is defined as a primary heart muscle disease characterized by systolic dysfunction and dilatation of the left or both ventricles in the absence of abnormal loading conditions(hypertension,valve disease)or coronary artery disease sufficient to cause global systolic impairment,usually leading to heart failure,ventricular/supraventricular arrhythmias,thromboembolism and sudden cardiac death(SCD).Reduced ejection fraction(EF)(EF<40%)or borderline preserved EF(ranged from41%to 49%),are both defined as heart failure clinically.Patients were included if the left ventricular end-diastolic diameter(LVEDD)>55mm(male)/50 mm(female)with left ventricular ejection fraction(LVEF)<50%,admission to echocardiography.The exclusion criteria of the study was patients with acute myocarditis,specific heart muscle disease,general systemic disease,significant coronary artery stenosis,hypertension(>160/100mmHg),valvular disease,and sensitivity/toxic reactions.All the patients were given standard medication according to the guideline recommendations during the period of hospitalization and after discharge.Clinical data Collection:Basic information including age,sex,medical histories,course of NIDCM,NYHA heart function classification,history of smoking and alcohol,medical history of diabetes,COPD and atrial fibrillation,and data regarding treatment were collected.Blood samples were taken from the enrolled patients for measurements at baseline.Laboratory measurements were conducted by the clinical laboratory of the First Affiliated Hospital of Zhengzhou University,including RDW,hemoglobin,serum N-terminal pro-brain natriuretic peptide(NT-pro BNP),serum sodium,renal function and total serum protein.LVEF and the size of cardiac chambers(left atrial and both ventricles)were calculated by 2-dimensional echocardiography using a digital imaging system(Vivid-7;GE Medical System,Willoughby,OH).All the data above were collected in the first three days of hospitalization.During the following-up period,adverse events after discharge,were recorded.We set all-cause death and re-hospitalization due to heart failure as the primary clinical outcomes.All patients were followed-up in telephone after discharge until April 2017 or the incidence of the two primary outcomes.Statistical analysis:Continuous variables were presented as medians(inter-quartile)ranges or the mean±standard deviations(SD).Categorical variables were presented as absolute and relative frequencies.Mean values in groups were compared using parametric statistics(Student's t test and analysis of variance)or nonparametric statistics(MannWhitney and Kruskal-Wallis'tests).The categorical variables were compared using general?~2 test or Fisher's exact test.We selected the Pearson's correlation analysis or Spearman's correlation analysis for univariate correlation analysis.To identify independent predictors of RDW,multivariate linear regression analysis was performed following univariate correlations.A multivariate Cox proportional hazards model was used to calculate risk ratios for independent predictors of mortality and re-hospitalization in continuous variables.To investigate the difference of survival rate and re-hospitalization rate of patients between the two groups,Kaplan-Meier were applied.Restricted cubic splines transformation and High-Low charts were completed by R-project version 3.4.2 and SPSS,respectively.The difference was statistically significant when P-value<0.05.ResultsBaseline characteristics of subjects:RDW of enrolled patients was ranged from12.1%to 21.4%,the median was[14.6(13.5,16.2)]%,and expression of RDW in 63patients(50.8%)was above the upper limit.With RDW>14.5%as the threshold,the enrolled patients were classified into RDW normal group and RDW elevated group.Between the 2 groups,there were significant difference in the comparisons of rate of utilization in spirolactone,levels of NYHA heart functional class,RVEDD,LVEDD,uric acid,Scr,N-Pro BNP,SBP,DBP and serum sodium(P<0.05).Correlation analysis between RDW and other clinical factors indicated that the levels of RDW was positively correlated with RVEDD(r=0.399,P<0.001),NT-pro BNP(r=0.490,P=0.027)and the rate of utilization in spironolactone(r=0.456,P=0.015).Prognostic value of RDW in patients with NIDCM:During the follow-up period,35 patients(35/124,28.2%)were died,the mean follow-up period was(13.0±5.3)months.The mortality rate in the RDW normal group and the elevated group were4.9%and 50.8%,respectively.A total of 73 patients went into hospital due to exacerbations(58.9%)with follow-up period(8.7±4.9)months,including 37.7%of patients in RDW normal group and 79.4%of patients in RDW elevated group.Kaplan-Meier survival analysis was used to evaluate the predictive ability of RDW on cumulative survival and re-hospitalization for patients with NIDCM.Results showed that patients with an elevated RDW on admission had significantly higher mortality and re-hospitalization rate compared with RDW normal group(Figure 1;P<0.001).In the univariate analysis and multivariable analysis,RDW remained a predictor of mortality(Table 3)and re-hospitalization(Table 4)in patients with NIDCM.Unadjusted and adjusted results were reported as odds ratios(ORs)with 95%confidence interval(CIs)(Figure 2).Especially,RDW(1%higher)was the prognostic factor for re-hospitalization(hazard ratio,1.19;95%confidence interval,1.06~1.34;P=0.005)and all-cause mortality(hazard ratio,1.51;95%confidence interval,1.21~1.87;P<0.001)after adjustment for other covariates in the Cox regression model.Restricted cubic splines transformation of RDW was performed after Cox regression analysis(Figure 3).The relationship between RDW and all-cause death was shown in Figure 3A.The plot of the log-relative hazard vs.RDW indicated a clear cutoff value at the point of 14%.Below the value of 14%,RDW is a protective factor for patients with NIDCM(P<0.05).When the expression of RDW was higher than value of 14%,the risk of mortality was significantly increased.(Figure 3A,P<0.05)When comes to the event of re-hospitalization,the figure shows no significance(Figure 3B).Following,the predictive ability of RDW on the risk of re-hospitalization was further analysis according to the quartiles of RDW.It was found that the risk of re-hospitalization was increased steadily with the higher quartiles of RDW after adjusted by age,sex,and study(Figure 4),HR was increased greatly when the expression of RDW was higher than 16%(adjusted HR=4.46;95%CI:2.10–9.51;P<0.05)when compared to those with the expression of RDW less than 13.4%.ConclusionIn summary,RDW was elevated in more than half of NIDCM patients(50.8%).When RDW increased by 1%,re-hospitalization of heart failure and all-cause mortality increased by 19%and 51%,respectively.Our study further investigated the independently predicting role of RDW for patients with NIDCM,elevation of RDW could provide useful information for the long-term prognosis of NIDCM.