Red cell distribution width (RDW) and increased risk of recurrent acute coronary syndrome

Objectives: Red cell distribution width (RDW) is associated with mortality in cardiopulmonary disorders such as coronary artery disease (CAD), acute coronary syndrome (ACS), heart failure, and acute pulmonary embolism. However, the little data that is available show the relationship between RDW and re-ACS after discharge in ACS patients. We aimed to investigate for relation between admission RDW and reACS related rehospitalization in ACS patients. Methods: A total of 400 consecutive patients with ACS were evaluated. In ROC curve analysis: optimal cut-off value of RDW to predict re-ACS was found as >14.0%, with 70% sensitivity and 62.5% specificity. Patients were categorized as having no increased (Group I) or increased (Group II) RDW based on a cut off value of 14.0%. Results: Mean age of patients was 63±12 years. Mean follow-up duration was 15±9 months and 80 patients rehospitalized with reACS. Among these 80 patients 24 (11%) patients belonged to Group I, and 56 (32%) patients were in Group II (p<0.001). Increased RDW > 14.0% on admission, presence of ST elevation MI, LV ejection fraction, and HDL cholesterol levels were found to have prognostic significance in univariate analysis. In multivariate Cox proportional-hazards model, only increased RDW > 14.0% on admission (HF=2.355, P=0.002), and previous ST elevation MI (HR: 1.906, P=0.024) remained associated with an increased risk of re-ACS. Furthermore, the mortality rate of the patients in the second group were significantly higher than those observed in the first group (4 (2%) vs 27 (15%), p<0.001). Conclusions: It seems RDW helps risk stratification in patients with ACS.


Introduction
Acute coronary syndrome (ACS) is a cardiovascular disease causing serious mortality and morbidity throughout the entire world (1,2).Although ACSrelated mortality rates were low in the last quarter, conditions such as re-ACS and stroke, which develop during the follow-up of these patients, still pose a major problem (3,4).Many clinical and laboratory parameters associated with mortality in patients with CAD were studied (5,6).However, affordable and easily accessible biomarker-based studies that are related to re-ACS are still scarce (7)(8)(9).
Red cell distribution width (RDW) is a hematological marker that is routinely analyzed and involved in hemogram, and is a parameter within which to evaluate the erythrocyte volume in circulation (10).Currently, RDW is primarily utilized to determine the type of anemia, and as assistant hemogram parametrics for the diagnosis of different forms of leukemia.However, the studies performed in the last 10 years determined that the prognosis of patients with CAD, heart failure (HF), acute myocardial infarction (AMI), and acute pulmonary embolism (APE) were associated with RDW (11)(12)(13)(14)(15).Moreover, RDW of patients with peripheral atherosclerosis (16), diabetes mellitus (17), and without a history of MI previously were shown to be related to the development of MI (18).
However, the relationship between RDW and re-ACS has not been simultaneously evaluated in all ACS subgroups.This study aimed to examine the relationship between admission RDW levels during hospitalization in patients with the diagnosis of UAP, non-ST elevation MI, and ST elevation, and rehospitalization in patients with the diagnosis of re-ACS after discharge.

Materials and Methods
In this cross-sectional cohort study, a total of 400 consecutive patients who were hospitalized and underwent coronary angiography between 2011 and 2014 due to ACS in our center were enrolled in the study.The exclusion criteria were as follows: previous coronary artery disease, chronic hepatic diseases, dialysis due to chronic kidney failure, diagnosis of malignancy, previous diagnosis or treatment for anemia and administration of erythrocyte suspension within the last six months.

Original Article
Zorlu A et al.Transthoracic echocardiograms were performed during index hospitalization within the first 24 hours in all of the patients.Echocardiographic examinations were performed via Vivid 7 system (GE Medical System) with 2.5-5 Mhz probes.The ejection fraction was calculated by Modified Simpson method was evaluated according to the most recent guidelines (20).Right ventricular (RV) dimensions were evaluated according to guideline (20), and hence, midcavity and/or basal RV diameter above and below the reference range in the apical 4-chamber view at end diastole were taken into consideration.The systolic pulmonary artery pressure (SPAP) was calculated by peak velocity of tricuspid regurgitation and estimated right atrial pressure (21).The study was performed in accordance with the Declaration of Helsinki for Human Research, and was approved by the institutional review board.

Statistical analysis
Continuous variables were expressed as mean ± SD or median (min-max) in the presence of abnormal distribution, and categorical variables as percentages.
Receiver operator characteristic curve analysis was performed to identify the optimal cut-off point of RDW (at which sensitivity and specificity would be maximal) for the prediction of re-ACS related rehospitalization.Areas under the curve (AUC) were calculated as measures of the accuracy of the tests.
We compared the AUC with use of the Z test.Patients with ACS were categorized as having no increased (Group I) or increased (Group II) RDW based on a cut off value.Comparisons between groups of patients were made by use of a χ2 test for categorical variables, independent samples t test for normally distributed continuous variables, and Mann-Whitney U test when the distribution was skewed.Kaplan-Meier curves were used to display re-ACS related rehospitalization in two patient subgroups, defined as having no increased (Group I) or increased (Group II) RDW based on a cut off value.We used univariate analysis to quantify the association of variables with re-ACS related rehospitalization.Variables found to be statistically significant in univariate analysis and potential other confounders were used in a multivariate cox proportional-hazards model with forward stepwise method in order to determine the independent prognostic factors of re-ACS.All statistical procedures were performed using SPSS software version 14.0 (SPSS Inc., Chicago, IL).A p value of 0.05 was considered as statistically significant.

Results
There were 400 consecutive patients (312 males, 88 females), admitted with ACS to a single tertiary coronary care center.Mean age was 63±12 years.There were 200 patients with ST elevation MI, 100 patients with non ST elevation MI and 100 patient with UAP.Mean hemoglobin was 14±2 gr/dl.
Receiver operator characteristic curve analysis of RDW was shown in figure 1.According to the ROC curve analysis: optimal cut-off value of RDW to predict re-ACS related rehospitalization was found as >14.0%, with 70% sensitivity and 62.5% specificity (AUC 0.702, 95% CI 0,654 to 0,746, Figure 1).
Comparison of two subgroups of patients with ACS along with electrocardiography, echocardiography and laboratory findings was summarized in Table 1.Most of the transthoracic echocardiograms were performed within the first 24 hours of emergency unit admission (at admission in most of the patients).Findings of echocardiographic examinations extending deadline (n=18) were not considered in the study, as, findings could have been changed.
Baseline characteristics of patients with ACS classified into two categories according to threshold RDW levels were presented in Table 1.The mean age of patients increased with elevated RDW levels.The LV ejection fraction was significantly lower in patients with high RDW levels, and the presence of RV dilatation and pulmonary hypertension were more frequent.Patients become more anemic with increased RDW levels, creatinine levels, and with decreased TG and LDL levels.The Gensini score increased in relation to the RDW level.However, differences in revascularization rates between the two groups of patients are not available.Mortality rates were statistically significantly higher in the second group (4 (2%) vs 27 (15%), p <0.001).In terms of drug use, there was no statistically significant difference between the two groups.
The patients were followed up for an average of 15 ± 9 months (range 1-36) and 80 patients were rehospitalized due to ACS.Among 80 patients who rehospitalized with reACS, 24 (11%) patients belonged to Group I, and 56 (32%) patients were in Group II (p<0.001,Table 1).According to Kaplan-Meier analysis, a significant difference was found between the two groups (having increased or no increased RDW based on a cut off value of 14.0%) in terms of re-ACS related rehospitalization rates (p<0.001, Figure 2).
Results of the univariate and multivariate Cox proportional-hazards analyses for reACS related rehospitalization were depicted in table 2. Increased RDW > 14.0% on admission, previous ST elevation MI, LV ejection fraction, and HDL cholesterol levels were found to have prognostic significance in univariate analsis.In multivariate Cox proportional-hazards model, only increased RDW ≥ 14.0% on admission (HF=2.355,%95 CI=1.363-4.069,P=0.002), and previous ST elevation MI (HR: 1.906, %95 CI= 1.087-3.343,P=0.024) remained associated with an increased risk of re-ACS related rehospitalization after adjustment for variables found to be statistically significant in univariate analysis and correlated with RDW level (age, presence of anemia, pulmonary hypertension, RV dilatation, gensini score, triglyceride, LDL cholesterol, and creatinine levels).

Discussion
The current study demonstrated that rehospitalization in patients with reACS after discharge was predicted by high levels of RDW during hospitalization in patients with the diagnosis of ACS independent of revascularization, drug usage and other clinical and laboratory parameters.Furthermore, it was determined that high levels of RDW were related to mortality, and poor functions of right sides of the heart and kidney.
It is well-known that prognosis in ACS is observed in the early term and mortality and morbidity rates increase due to reasons such as developing reMI, stroke, or decompensated HF in patients after discharge.Therefore clinical and laboratory factors that might predict the recurrent major cardiovascular events are required.In addition to the major risk factors that are known in the development of cardiac events, many studies and meta-analysis in recent years have shown that parameters such as Lp(a), and thrombotic and inflammatory factors (hyperhomocysteinemia, hsCRP, fibrinogen) play an important role in initiation and the progression of atherosclerosis (22)(23)(24)(25).Furthermore, the markers that are associated with reACS have also been identified in recent years.Rubattu et al. showed that the 2238C ANP gene variant is associated with recurrent ACS (7).Kume N et al. determined that lectin-like oxidized low density lipoprotein receptor-1 (LOX -1) in circulation predicted recurrent ACS and mortality (8).Moreover, Ping Wang et al. showed that high RDW levels in patients with a history of ST-elevated MI and primer PCI predicted a new MI development (18).
RDW is a parameter that is measured as a part of complete blood count and shows the volume ratio of red blood cells in circulation (26).RDW is used to estimate the diagnosis and prognosis of hematological diseases (such as leukemia) and the classification of anemia (27).Studies in recent years have shown that cardiovascular and pulmonary diseases such as CAD, HF, APE, and also AMI are associated with mortality and morbidity (11,13,15,28).Moreover, the relationship between cardiovascular mortality in the general population and high RDW was also demonstrated (29).Finally, Hairong Ren et al. (30) showed that the highness of RDW independently predicted mortality and ACS in the one-year follow-up in patients with stable angina pectoris.
There are a number of cardiovascular and pulmonary disease mechanisms explaining high RDW levels.Increased RDW occurs by anemia developing as a result of nutritional deficiency comorbid diseases, and renal dysfunction in cardiovascular and pulmonary diseases (31,32).In addition, oxidative stress, inflammation, and released cytokines secondary to inflammation damages the iron metabolism, reduces the life span of erythrocytes, reduces the bone marrow response to erythropoietin, and increases Acta Med Anatol 2015;3(2):39-46 44 RDW (33)(34)(35).Another reason is that erythrocyte progenitor cells are stimulated by neurohumoral and adrenergic system activation, depending on decreased erythropoiesis; as a result, RDW increases (36).In addition, oxidative stress has been associated with cigarette smoking; RDW in smokers is higher than in non-smokers (37).A positive correlation between high RDW level and high total cholesterol level that was contained by the erythrocyte membrane in ACS patients was demonstrated (38).These mechanisms are thought to contribute to the development of atherosclerosis.Erythrocytes contain large amounts of free cholesterol (39), and pathological changes in the erythrocyte membrane and spread of inflammatory cascade causes erythrocyte aggregation in the athermanous plaque and the storage of free cholesterol (40).Aggregated erythrocytes also lead to plaque instability.When stable cardiac patients are compared to ACS patients, the presence of high cholesterol in the erythrocyte membrane in ACS patients supports this thesis (41).
Many studies have shown that RDW levels are correlated with EF.In contrast Arbel Y et al. stated that there was no correlation with EF and RDW (42,43).The current study has shown that RDW levels are correlated with EF.Some studies demonstrated high RDW levels were associated with right ventricular dysfunction (15,44), while others that refute this association (45) are available.In the current study, high RDW levels were found to correlate with poor right ventricular function.Afsar B et al. (46) showed that RDW was associated with poor kidney functions, the results of which are compatible with the results of the current study.Ma FL et al. (47) revealed that high RDW levels are associated with a high Gensini score (severe CAD).Our study revealed a positive correlation between the RDW and Gensini score.

Conclusion
According to the results of our study, admission RDW levels in patients hospitalized with ACS have been shown to be strongly associated with predicting rehospitalization with the diagnosis of ACS after discharge, independent of revascularization.The risk stratification of patients can be performed by predicting the re-ACS risk in patients with the diagnosis of ACS that have been scheduled for discharge after being hospitalized.It is thought that initiating intense, maximal medical therapy for patients with high RDW levels may be required and these patients should be closely monitored.

Table 1 :
Comparison of patients with ACS grouped into two categories according to optimal cut-off value of RDW level for reACS-related rehospitalization along with baseline characteristics, and current electrocardiography, echocardiography, and laboratory findings.

Table 2 :
Univariate and multivariate Cox proportional hazards analyses of reACS related rehospitalization All the variables from Table1were examined and only those significant at P < 0.05 level and correlated with RDW are shown in univarite analysis.The multivariate Cox proportional hazards model with forward stepwise method included all univariate predictors and those with correlated RDW level.CI: Confidence interval; HR: Hazard ratio, Abbreviations in Table1.Optimal cut-off point of RDW (at which sensitivity and specificity would be maximal) for the prediction of re-ACS related rehospitalization was defined with ROC curve analysis.Patients with ACS were classified according to this RDW cut-off value.Group I consisted of patients with RDW ≤ 14.0% (n=224) and Group II consisted of patients with RDW > 14.