There are two main findings of this study. First, with increasing values of RDW, there is an increase in the rate of patients with serious comorbidities such as COPD, PVD, diabetes treated with insulin, atrial fibrillation and heart failure in the entire population. Second, the RDW was associated with mortality, even after adjusting for clinical echocardiographic and hemodynamic variables in the whole population and in various subgroups. Mortality in the patients with the highest RDW values was almost 4-fold higher than in patients with the lowest RDW values. Similar results were obtained by Fatemi O. and Tonelli M. et al., who observed a graded relationship between RDW quartiles and mortality in patients with various forms of coronary artery disease [4, 11], and by Patel V.K., who reported an increase in mortality across RDW quintiles in the general population . In a recent study, Ren H. et al. reported that similar trends of mortality and RDW may be present in patients with stable coronary artery disease because they registered 8 deaths (2.27%) vs. 2 deaths (0.51%)  in patients with RDW values in the highest and lowest RDW quartiles, respectively. Our analysis of a larger population with a longer follow-up period and 233 registered events confirms those findings.
RDW as a marker of disease burden
An increased percentage of patients with serious comorbidities compared to patients with lower RDW values suggests that RDW is a universal marker of disease burden. Data from analyses referring to the wide spectrum of diseases seem to confirm that finding [3, 18–28]. Associations between higher RDW levels and CKD are quite easy to explain because anemia, which is frequently found in patients with impaired renal function [29, 30], is associated with increased RDW values. Moreover, RDW values are often used for anemia classification . An explanation similar to that for CKD may hold for heart failure because Jankowska E et al. showed that iron deficiency develops during the progression of heart failure . In our study, the frequency of heart failure and the percentage of patients with advanced heart failure symptoms were higher in patients with RDW values within the 4th quartile. The association of RDW with other comorbidities such as COPD, diabetes and peripheral vascular disease may be more difficult to elucidate. Possible explanations come from publications describing the increased inflammatory status and increased oxidative stress in those conditions [33–38]. Therefore, in more advanced stages of atherosclerosis, COPD and diabetes, the detrimental effects of oxidative stress on erythrocyte membrane fluidity affects the lifespan of red blood cells, which in turn leads to higher RDW values . However, Fornal M et al. and Lippi G et al. [40, 41] reported the existence of a potential link between inflammatory biomarkers and RDW values that may also be of importance, because the inflammation may impair iron metabolism and inhibit both the production of and the response to erythropoietin [18, 42]. Veranna V. et al. reported that RDW values of 12.6% and increased CRP levels above 3 mg/dl are associated with a higher risk of mortality in a cohort free of coronary heart disease . Another interesting observation is the lower frequency of multivessel coronary artery disease (MVD) in patients with RDW values in the 1st quartile compared to the other quartiles, which is in concordance with results of Isik T. et al. and MA F-L [44, 45]. Those findings may indirectly confirm the association of increasing values of RDW with extensiveness and possibly the duration of the atherosclerotic process and the role of RDW as a marker of the disease process.
Red blood cell heterogeneity as a potential causative factor
The association between RDW values and comorbidities does not entirely explain the increased mortality in patients with the highest RDW values because RDW remained highly significantly associated with mortality after adjusting for clinical echocardiographic, hemodynamic and laboratory parameters in the entire cohort and in subgroups, although in our study it did not improve risk prediction as estimated by NRI and IDI measures. There have been however studies showing that RDW improves prediction of bleeding after acute coronary syndromes  and mortality in kidney transplant recipients .
Currently, it is not clear why higher RDW levels are so strongly associated with worse long term prognoses in various diseases. Luneva O.G. et al. provided insight into the pathophysiology of the relationship between mortality and RDW values by finding a significant correlation between RDW values and the cholesterol content of erythrocyte membranes, which also determines erythrocyte membrane fluidity . It has also been reported that greater variation in RDW is associated with impaired blood flow through the microvascular system, which may cause tissue hypoxia, even in patients without anemia .
Strengths and limitations
A limitation of this study is the retrospective design. Nonetheless, the potential disadvantages of this retrospective analysis are diminished by the fact that the patient data are inputted into an electronic database from report forms filled out by the attending physician upon the patient’s admission to our center. Other limitations include a lack of iron status and other biomarkers such as high sensitivity troponins.
Strengths of this study include large cohort, detailed data on clinical, echocardiographic hemodynamic and laboratory parameters, and long follow-up period with very little patients lost to follow-up.