The Prognostic Role of Red Blood Cell Distribution Width in Coronary Artery Disease: A Review of the Pathophysiology

Red blood cell distribution width (RDW) is a measure of red blood cell volume variations (anisocytosis) and is reported as part of a standard complete blood count. In recent years, numerous studies have noted the importance of RDW as a predictor of poor clinical outcomes in the settings of various diseases, including coronary artery disease (CAD). In this paper, we discuss the prognostic value of RDW in CAD and describe the pathophysiological connection between RDW and acute coronary syndrome. In our opinion, the negative prognostic effects of elevated RDW levels may be attributed to the adverse effects of independent risk factors such as inflammation, oxidative stress, and vitamin D3 and iron deficiency on bone marrow function (erythropoiesis). Elevated RDW values may reflect the intensity of these phenomena and their unfavorable impacts on bone marrow erythropoiesis. Furthermore, decreased red blood cell deformability among patients with higher RDW values impairs blood flow through the microcirculation, resulting in the diminution of oxygen supply at the tissue level, particularly among patients suffering from myocardial infarction treated with urgent revascularization.


Introduction
Red blood cell distribution width (RDW) is a parameter routinely measured by most modern hematology analyzers. RDW is defined as the quotient of standard deviation of red blood cell volume and its mean volume and is expressed as a percentage according to the following formula: RDW = (standard deviation of red blood cell volume/mean cell volume) × 100. Higher RDW values reflect greater variations in red blood cell volume [1].
One of the first studies to assess the role of RDW in cardiovascular disease was published by Felker et al. in 2007. The authors noted the usefulness of RDW as a prognostic marker among patients with heart failure (HF) [2]. Subsequent studies have confirmed the significance of RDW as a predictor of mortality both in the general population [3] and in patients with various diseases, including peripheral artery disease (PAD) [4], chronic obstructive pulmonary disease (COPD) [5], and kidney failure [6][7][8]. In the literature, there exist increasing amounts of data describing the link between RDW and prognosis in patients with stable coronary artery disease (SCAD) [9], including patients undergoing percutaneous coronary intervention (PCI) [10] and patients suffering from myocardial infarction (MI) [11,12].
The aim of this review is to describe the prognostic utility of RDW in patients with coronary artery disease (CAD) and to elucidate the mechanism underlying the relationship between elevated RDW values and poor patient prognosis in this particular group of patients. 2 Disease Markers and diagnostic role of RDW in patients with CAD using the following keywords: red cell distribution width; RDW; coronary artery disease; myocardial infarction; acute coronary syndrome. Additionally, we have searched reference lists of publications in this field. The most important and appropriate studies investigating the prognostic and diagnostic value of RDW in patients with CAD are summarized in Table 1.
One of the studies that assessed the prognostic role of RDW was conducted at our center. We demonstrated that RDW was an independent risk factor for long-term mortality in patients undergoing PCI for SCAD [10], and CAD patients with elevated RDW values more frequently suffered from concomitant diseases such as PAD and COPD [10]. Furthermore, RDW itself correlates with both the severity and the complexity of coronary artery atherosclerosis, as determined using the SYNTAX [43] and Gensini scores [40].
Tonelli et al. determined that RDW was a risk factor for MI, stroke, and symptomatic HF in patients with CAD [9]. Elevated RDW levels are also associated with increased inhospital and long-term mortality among patients suffering from MI [11,12]. Lippi et al. observed that RDW had diagnostic value in patients admitted to the intensive care unit for chest pain suggestive of acute coronary syndrome. Combined measurements of both troponin T and RDW have allowed for diagnosing MI with greater sensitivity than the analysis of troponin T alone [36]. In patients with non-ST elevation myocardial infarction, RDW may be used to predict the occurrence of fragmented QRS complexes noted on electrocardiography [46] and the absence of collateral circulation on coronary angiography [47]. Additionally, there exist publications that describe the relationship between RDW and the lack of tissue reperfusion in patients with MI treated via PCI [44,57].
The results of large, prospective studies with long-term follow-up periods (Tromsø and National Health and Nutrition Examination Survey) show that elevated RDW values increase the risk of MI and mortality due to CAD in the general population, regardless of other known CAD risk factors [67,69], including the risks of MI and mortality among elderly patients without aging-associated diseases [3].
One of the most important limitations affecting the longterm outcomes of CAD invasive treatment is restenosis [70] which occurs more frequently in patients with elevated RDW values, which is the case following both bare-metal [61] and antimitotic drug-eluting stent implantation [64]. RDW is also valuable in assessing the risk of major bleeding complications in patients undergoing PCI [60], as well as the risk of contrast-induced nephropathy [65]. In patients undergoing coronary artery by-pass grafting, RDW is a risk factor for atrial fibrillation following cardiac surgery [59].
One limitation to the clinical usefulness of RDW in predicting adverse clinical outcomes is its moderate sensitivity and specificity [12]. However, these parameters are often not worse than any other laboratory parameters used in risk stratification, including C-reactive protein (CRP) [67,71]. Additionally, there are no unambiguous RDW cut-off values. In papers concerning this problem, the cut-off values vary depending on the population and adverse events studied [72]. The potential use of RDW as a predictive factor for cardiovascular events appears to reside in its utilization as an element of various risk scores.
The main limitation of the vast majority of cited studies is that they were observational and described only the statistical relationship between elevated RDW value and outcomes of patients with CAD, but not the pathophysiological mechanism explaining that phenomenon. Moreover, only a few published studies included factors influencing the hematopoiesis, that is, levels of folic acid, vitamin B12, markers of inflammation, and iron status as potential confounding factors [72,73].
In summary, RDW is a significant predictor of both allcause mortality and adverse cardiovascular events in patients with CAD. Increased values of this parameter are associated with greater numbers of comorbidities and a higher likelihood of complications among patients with CAD treated via PCI.
In the following sections, the potential mechanisms explaining why elevated RDW levels are a strong, negative predictive factor among patients with CAD will be discussed.

The Reasons for the Poor Prognosis Observed in Patients with CAD with High RDW Levels
The influence of RDW on prognosis among patients with cardiovascular disease has been extensively studied [9][10][11][12]. Nonetheless, the reasons for the poor prognosis in this patient group remain unclear. For instance, it has not been determined whether RDW is only a marker of the severities of various disorders or if there is a direct pathophysiological relationship among anisocytosis, CAD, and poor prognosis in patients with CAD. Most likely, numerous factors impairing bone marrow hematopoietic function, which are identical to the factors that worsen the prognoses of patients with CAD, play integral roles in this process.

Anemia, Iron, and RDW.
Anemia is a well-documented mortality risk factor among patients with CAD and is prevalent in cases of elevated RDW values [74,75]. However, elevated RDW values increase mortality in patients with CAD regardless of their baseline hemoglobin levels [10,16]. Furthermore, RDW has prognostic value in patients without anemia [10]. On the other hand, Salisbury et al. indicated that baseline RDW is associated with development of moderatesevere anemia during hospitalization in patients with MI and without concomitant anemia at admission [76]. It is not surprising that RDW is affected by iron metabolism [73]. Grammer et al. determined that reduced iron stores, regardless of hemoglobin concentrations, increased the likelihood of coronary artery atherosclerosis [77]. Furthermore, Ponikowska et al. determined that disturbances in iron metabolism increased mortality among patients with CAD and diabetes mellitus [78]. Perhaps iron status and low hemoglobin levels are only partially responsible for the poor prognoses observed among patients with elevated RDW levels.   Retrospective 293 patients with SCAD who underwent DES implantation RDW level at both admission and follow-up is an independent predictor of ISR.

Lipid
[64] Akin et al. (2015) Prospective, cross-sectional 630 patients with STEMI who underwent primary PCI Authors confirmed that RDW is an independent risk factor for the development of CI-AKI. Prospective, cohort study 26,820 subjects (aged 45-73) without history of MI or stroke RDW is associated with increased incidence of fatal ACS, but not with incidence of nonfatal ACS. profiles [79,80]. Some insight into the relationship between RDW and lipid disorders was provided by Tziakas et al., who described a link between RDW and total cholesterol erythrocyte membrane (CEM) levels [81]. CEM level increases are responsible for the deterioration of cell deformability, which affects the lifespans of circulating erythrocytes, and this results in greater cellular turnover and elevated RDW values [82][83][84]. Previous studies have confirmed that once the necrotic core of the plaque accumulates erythrocytes, elevated CEM levels may result in plaque instability, which suggests that red blood cells may actively contribute to both plaque growth and plaque destabilization [85][86][87].
Lipid disorders decrease red cell membrane fluidity, and higher CEM levels result in the deterioration of blood flow through the microcirculation [88,89]. This mechanism may explain the well-documented relationship between red blood cell rheology and the lack of tissue reperfusion following PCI in patients suffering from MI [56,90]. This effect may also explain the slow flow phenomenon observed in the epicardial coronary arteries in symptomatic patients without coronary artery stenosis [91].
Previous studies have noted that statin therapy increases erythrocyte deformability [89,92,93]. However, Kucera et al. demonstrated that 12 weeks of atorvastatin therapy did not affect RDW levels despite improved lipid profiles [80]. It is possible that the statin therapy in question was not administered long enough to decrease erythrocyte membrane cholesterol concentrations (the mean erythrocyte lifespan is 115 days) [94].

Chronic Inflammation and RDW.
Another explanation for the relationship between RDW and prognosis may be chronic inflammation. It is believed that even low-intensity inflammation plays a crucial role in atherogenesis and may be responsible for platelet activation [95,96]. Lippi et al. described the relationship between RDW and inflammatory markers such as the erythrocyte sedimentation rate and high sensitivity CRP [97]. In previous studies, RDW correlated with interleukin-6, soluble tumor necrosis factors I and II receptor concentrations, and fibrinogen levels [73,83,98]. Additionally, chronic inflammation results in disorders of iron metabolism and decreases both the production of and bone marrow responsiveness to erythropoietin, resulting in impaired hematopoiesis and increased RDW levels [98][99][100]. The significance of both anemia and iron metabolism has been discussed previously.

Glycemic Disturbances and RDW.
Veeranna et al. observed the correlation between HbA 1C levels (glycosylated hemoglobin) and RDW levels in patients without diabetes mellitus [101], and Lippi et al. observed the existence of a relationship between HbA 1C and RDW in an unselected population of elderly patients [102]. Additional studies have noted an increased prevalence of diabetes complications such as nephropathy and cardiovascular disease in patients with diabetes and elevated RDW levels [103,104]. Garg et al. demonstrated that HbA 1C levels had an impact on CAD severity in patients without diabetes; therefore, these levels may be considered a mechanism linking RDW values to impaired glucose metabolism [105].

Vitamin D 3 Deficiency and RDW.
Another factor potentially affecting RDW is vitamin D 3 deficiency, a wellestablished CAD risk factor [106]. Vitamin D 3 deficiency is responsible for both cell proliferation and erythropoiesis, and vitamin D 3 concentrations in the bone marrow are more than two hundred times greater than in the blood. Even a minor decrease in serum vitamin D 3 levels may result in the derangement of bone marrow erythropoiesis [107,108].

Oxidative Stress and RDW.
Oxidative stress is responsible for shortening the lifespan of red blood cells, which intensifies both the production and the release of young cellular forms into the circulation, which is reflected by increased RDW levels [109]. Oxidative stress also generates oxidized low-density lipoprotein forms, which play an important role in atherogenesis [110]. Kobayashi et al. demonstrated that using a vitamin E-bonded hemodialyzer resulted in decreased RDW values in a group of patients with endstage kidney disease undergoing hemodialysis. This effect was absent in patients dialyzed without vitamin E-bonded hemodialysis membranes [111]. The authors mentioned that the decreased RDW levels were accompanied by reduced whole-blood viscosity [111].

3.7.
Renal Failure and RDW. Impaired kidney function increases mortality among patients with CAD [98,112], and the relationship between low glomerular filtration rate, microalbuminuria, and elevated RDW levels has been demonstrated in previous studies [6,8]. Impaired kidney function, however, is most likely not a separate mechanism linking elevated RDW values to poor patient prognosis in CAD [7], because, among patients with chronic kidney disease, chronic inflammation, greater oxidative stress, lipid disorders, vitamin D 3 deficiency and anemia, and increased RDW levels are often noted [6,8,111,113,114].
3.8. Summary. The above-mentioned data indicate a correlation between RDW and other known atherosclerosispredictive factors, although it is impossible to clearly identify the mechanism by which high erythrocyte anisocytosis serves as a negative prognostic marker in patients with CAD. In our opinion, the prognostic value of RDW results primarily from the negative impacts of inflammation and oxidative stress, as well as those of iron and vitamin D 3 deficiency, on bone marrow erythropoiesis. Additionally, concurrent red blood cell deformability diminution may result in impaired flow through the microcirculation. It is also impossible to unambiguously ascertain which concomitant factors, including lipid, glycemic and iron metabolism disturbances, anemia, vitamin D 3 deficiency, oxidative stress, inflammation, and the diminution of erythrocyte membrane deformability, are the primary causes of the poor prognoses observed in patients with CAD. In the authors' opinion, the predictive utility of RDW results from the summation of each of the above-mentioned factors' negative impacts on bone marrow 8 Disease Markers erythropoietic function. Therefore, the prognostic value of RDW reflects the intensification of these phenomena.

Conclusions
RDW is an important risk factor for both mortality and cardiovascular events in patients with SCAD or acute coronary syndrome. It has not yet been determined whether anisocytosis is the cause of the poorer prognosis observed among these patients or if it is simply a marker of multiple pathological states connected with said prognosis. In contrast to the markers of inflammation and oxidative stress, which are not routinely analyzed, RDW provides valuable information concerning prognosis in patients with CAD.

Conflict of Interests
The authors declare no conflict of interests regarding the publication of this paper.