Our study demonstrated that RDW is a good prognostic marker in patients with HF and DM with respect to the study endpoint. We also showed that RDW longitudinal changes in diabetics differ significantly from the non-diabetic group.
Red blood cell distribution width is a widely available and inexpensive test, which is performed as part of the complete blood count. Previous studies have shown that higher levels of RDW were associated with poor outcome in a number of pathologic states such as HF, coronary artery disease and metabolic syndrome but also in the general population. The presence of comorbidities in patients with HF is not unusual. Among them, DM is a common disorder in HF patients. To our knowledge, data on prognostic value of RDW in patients with DM and HF are scarce.
RDW and diabetic status
Based on the current bibliography, RDW is a marker of inflammation and prognosis in patients with DM [
29,
30]. The association between DM and RDW has been initially examined by Subharshree [
31] in a cross sectional study, which showed that BNP correlated well with RDW in diabetic patients with HF. Engström et al. [
30] showed that low RDW was associated with a markedly increased risk of developing DM. Low RDW was also related to higher waist circumference, glucose, insulin and triglyceride concentrations. On the contrary, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW. Malandrino et al. [
35] investigated the relationship between RDW and DM complications (microvascular and macrovascular) in a population of 2.497 diabetics and concluded that higher RDW values were associated with increased probability of developing vascular complications, HF, myocardial infarction (MI), stroke and nephropathy. Acosta et al. [
36] reported shortened half-life of red blood cell in DM.
It is well established that the RDW values become elevated under conditions of increased red cell destruction or ineffective red cell production [
1]. Nevertheless, the pathophysiological path of increased RDW in HF syndrome remains unknown. A number of potential mechanisms have been proposed such as nutritional deficiency (vitamin B12, ferrum or folic acid), bone marrow depression or inflammation [
1,
37] leading to red blood cells lifespan extension, as a homeostatic adaptation [
38]. Thus, in HF, RDW is considered a prognostic marker, which may reflect an underlying inflammatory process [
39]. Importantly, inflammation is a common finding in patients with DM [
40,
41] and that is probably why DM is called “proinflammatory state” [
42]. Notably, in our study HF patients with DM manifested significant higher values of ferritin (which is considered as an acute phase protein of inflammation) [
43] and WBC versus those without DM. Sherif et al. [
44] suggested that RDW could be used as a marker of inflammation in type 2 DM. On top of this, our hypothesis was that patients with concomitant HF and DM would have different patterns of RDW changes against those with HF but without DM due to higher inflammatory burden. Inflammatory conditions, such as DM, due to multiple pathophysiological mechanisms lead to red blood cells deformation [
43]. In particular, the latter lose their typical discoid shape and membrane elasticity [
45].
The undesirable effects of high glucose levels are reflected in erythrocytes in multiple ways such as rearrangement of erythrocyte membranes, defects in Hb oxygen binding activity, alterations of mechanical features of the membrane and general aspects of the cell as well [
46,
47]. In particular, RBCs in DM patients manifest a rigid membrane with decreased deformability, increased osmotic fragility and enhanced aggregation. In addition, the impaired Na+/K+-ATPase activity leads to electrolyte disturbances, resulting in an increase in the cell size and increased osmotic fragility which, in turn, contributes to the development of microvascular complications. Furthermore, microscopic examination and state of the art technological measurements of the RBC’s in DM patients reveal augmented aggregate shape and size when compared to healthy controls and reduced deformability. The latter results in increased blood viscosity and probable increase in shear stress on the endothelial wall [
47,
48].
Pretorius et al. have shown not only that RBCs in type II DM have an altered shape (lose their normal discoid shape and adopt a skewed morphology), and a decreased membrane roughness [
45,
49], but also, that they can promptly adapt in a changed environment, including during an addition of glucose to healthy RBCs [
49,
50]. The same authors have interestingly reported that the axial ratio of the RBCs from DM patients was significantly greater against that of matched controls, as seemed to occur in a variety of inflammatory diseases [
49,
51‐
53] and raise the question of the probable prognostic and diagnostic significance of these findings. Similarly, Berndt-Zipfel et al., showed that RBC deformability was also altered in type II DM, and that an improved RBC deformability correlated with improved glycaemic control [
54]. Apart from RBC’s structure, a number of studies suggest that RBC rheology is also altered in type II DM [
49,
55,
56].
Recently, Nigra et al. [
57] reported that hyperglycaemia affected the human RBC’s by altering the content and distributions of three tubulin isotypes, resulted in reduction of erythrocyte deformability and osmotic resistance. Although, tubulin is not a major protein by volume in RBC’s, it plays a significant structural role and regulates the enzymatic activity such as Na+/K+-ATPase and PMCA [
58,
59]. The findings by Nigra et al., suggest that high glucose concentrations promote tubulin acetylation and its translocation to the membrane, and that this tubulin is involved in regulation of RBC’s deformability and osmotic fragility. This interplay among inflammation and unfavorable effects of high glucose levels on circulating erythrocytes shape, size and mechanical features can have an impact on RDW values. Longitudinal changes of RDW in the group of diabetics were significantly different compared to the non-diabetic group suggesting that inflammation may play a pivotal role in RDW changes. In summary, although RDW can be used for the risk stratification of HF patients with or without DM, it shows different variation patterns with time when we compare these groups.
The presence of anemia is associated with a special risk in patients with any form of proatherosclerotic condition and heart disease [
60]. Despite the fact that clinical and hemodynamical changes due to acute, short-lasting anemia are reversible, chronic anemia can lead to cardiac enlargement and left ventricular hypertrophy due to volume overload [
61]. Anemia is considered to be a mediator and a marker of a poor outcome in HF [
60,
62], a risk factor for ischemic heart disease, and often coexists in patients with acute coronary syndromes [
63]. Notably, in patients with stable coronary artery disease, higher RDW is a strong and independent prognostic marker of mortality [
8]. In our study, RDW was an independent, to anemia, prognostic factor for death or rehospitalization.
Study limitations
The sample size of diabetic patients that enrolled in the study was not large (71 patients), albeit every patient not met the study endpoint, had five measurements (admission, discharge, 4, 8 and 12 months). This means that the results should be interpreted under caution and used as a basis for larger studies.