Cardiovascular disease (CVD), such as congestive heart failure, hypertension, arrhythmia, and coronary artery disease, has been reported to be common in chronic obstructive pulmonary disease (COPD) patients.1–3 Therefore, COPD is known to be associated with cardiovascular morbidity and mortality.4 The most obvious explanation for the high cardiovascular morbidity and mortality rates seen in COPD patients is the high prevalence among this group of smoking and other known risk factors for CVD.4 In addition, COPD is associated with oxidative stress, and inflammation that may also initiate or worsen co-morbid diseases, such as CVD.5

Red cell distribution width (RDW) is a measure of the variability in size of circulating erythrocytes, and is routinely reported as a component of a complete blood count in the differential diagnosis of anemia.6 Recently, studies have reported that RDW might provide useful information for the prognosis of patients with CVD7–10 as well as for those with noncardiac diseases, including stroke and pulmonary hypertension, and also in the general population.11–13All these studies hypothesized that higher RDW levels might reflect an underlying chronic inflammation, which would result in an increased risk of CVD and increased mortality.

COPD also has a systemic inflammatory effect. The inflammatory process may extend beyond the pulmonary system, resulting in a state of persistent low-grade systemic inflammation which has been implicated in various complications of COPD including cachexia, CVD, and arrhythmias.5,14,15 Inflammation has been proposed as a key element in the association of COPD and CVD. It can be concluded that RDW levels, which is considered to be a marker of inflammation, may be elevated in patients with COPD as well as in CVD. Two recent studies have reported that high RDW levels in patients with COPD correlated with right ventricular dysfunction and overall survival.16,17

Smokers also have systemic inflammation.18 Clinical and experimental studies have noted that systemic markers of inflammation such as C-reactive protein (CRP), fibrinogen, interleukin-6, soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 are elevated in smokers.18 Only 1 study found high RDW levels in smokers.19

Very few studies in COPD patients have measured RDW levels. In this study, we aimed to find; (1) RDW levels in COPD patients, (2) the effect of biochemical, nutritional, cardiac and respiratory parameters, and of smoking on RDW levels in patients with COPD, (3) the effect of smoking on RDW values in healthy people, and (4) the benefit of RDW, as a routinely available marker, as a predictor of CVD in COPD patients.

Patients with COPD had significantly higher RDW values compared with control subjects (patients with COPD, 15.04±2.3; range, 10.4–24.5; control subjects, 13.8±2.5; range, 10–17.2; p<0.001) (Table 1) (Fig. 1). Seventy patients (40%) and 23 (11%) control subjects had an RDW>15.5%.

Fig. 1.

The RDW values were higher in the COPD group than in the controls [15.04±2.3 vs 13.08±2.5, P=0.01].

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In COPD patients, RDW levels positively correlated with CRP levels (r=0.27, P=0.001), RVD (r=0.24, P=0.001), PAH (r=0.1, P=0.02), presence of CVD (r=0.24, P=0.002), and inversely correlated with hemoglobin (Hgb) concentration (r=−0.26, P=0.01), and serum albumin levels (r=−0.23, P=0.04) (Table 2). In healthy population, correlation analyses showed a significant correlation between RDW and the cigarette pack years (r=0.57, p<0.001), and inversely correlated with Hgb concentration (r=−0.38, P=0.01) (Table 2).

Comparing patients with elevated (>15.5%) RDW values and nonelevated (≤15.5%) RDW values showed that the former were more likely to have higher CRP and PaCO2 levels, and lower FEV1 levels. In addition RVD, PAH, and presence of CVD were significantly higher in patients with elevated RDW (Table 3). In the healthy population, RDW values were significantly higher in smokers compared to non-smokers (Table 4). Additionally, in healthy subjects, only pack-year of smoking was statistically significant between those with high RDW levels and not. In COPD patients, univariate analysis showed elevated (>15.5%) RDW values were most closely associated with higher CRP levels (P=0.001), higher PaCO2 levels (P=0.02), lower Hgb levels (P=0.01), presence of PAH (P=0.1), presence of CVD (P=0.001), and presence of RVD (P=0.004). In the multivariate analysis, patients with an elevated RDW value were significantly more likely to have presented CVD (P=0.01), and RVD (P=0.02) (Table 5). ROC analysis showed 16.9 RDW value is as optimum cut-off value for diagnosis of RVD. When using this cut-off value, the sensitivity and specificity of RDW in diagnosis of RVD was 78% and 88.7%, respectively (Fig. 2).

Fig. 2.

Receiver operating characteristic curve. Levels of RDW, obtained before echocardiography, were predictive for the presence of RVD with a sensitivity of 71% and specificity of 88%, with a cutoff value >16.9 (RDW, red cell distribution width; RDV, right ventricular dysfunction).

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In the last few years, numerous studies have shown that RDW is a strong prognostic factor for all-cause mortality and CVD events in patients with a history of heart disease or chronic heart failure.7–10 In addition, RDW is strong predictor of all-cause mortality in population cohorts.10,11,13 All these studies suggest that the pathophysiology leading to increased RDW may reflect underlying chronic inflammation, which would result in an increased risk of CVD and increased mortality.5,14,15 We hypothesized that a chronic inflammatory state may be a mechanistic link between higher RDW and in COPD patients with CVD. In the present study, we have shown that COPD patients have elevated levels of RDW compared to controls. An addition, RDW was found to be an independent predictor of CVD in COPD patients.

Increased RDW is the result of heterogeneity of erythrocyte size and erythrocyte fragmentation in the circulation.6 Factors that contribute to increased erythrocyte size heterogeneity include iron or vitamin B12, folate deficiency, decreased erythrocyte life span, impaired erythropoiesis, or blood transfusion.6 Inflammation can also elevate RDW levels.22,23 Very recently, studies have shown that increased RDW values are also associated with adverse outcomes in CVD as well as noncardiovascular disease states, even in patients with heart failure, pulmonary hypertension, pulmonary embolism, sleep apnea, and in patients in the intensive care unit.7,9,12,13,24–26 Elevated RDW levels have also been strongly associated with increased risk of death and cardiovascular disease (CVD) events in middle-aged and older adults.13,27 In the 2 studies focusing on RDW levels in COPD published to date,16,17 the authors concluded that RDW could be a marker of long-term prognosis and RVD. We found in our study that RDW levels were significantly higher in patients with COPD compared to healthy subjects. Our primary goal was not to discriminate COPD patients from healthy subjects. However, the discriminative capacity is not high when comparing COPD patients and healthy subjects. In line with Dincer et al.,17 we found high RDW levels to be associated with CVD in patients with COPD.

CVD is more common among patients with COPD than in the general population.4 It is also a major risk factor for the development of CVD. Additionally, hypoxemia, oxidative stress and systemic inflammation are thought to contribute to the development of CVD in COPD.4,5 Through all these pathways, COPD has a potential link with CVD from the point of view of inflammation, atherosclerosis, and endothelial dysfunction.28 Inflammatory cytokine release in COPD could affect bone marrow function, and erythropoietin-induced erythrocyte maturation is inhibited, thus elevating RDW.22 Therefore, higher RDW levels might reflect an underlying chronic inflammation, which would result in an increased risk of CVD in COPD patients. In the present study, we found that CRP and RDW are significantly correlated. This finding may show a possible link between inflammation in COPD and RDW values. Co-existing CVD was detected in 34% of COPD patients in this study. We also concluded that the primary cause of high RDW levels in COPD patients was co-existing CVD.

Pulmonary hypertension (PH) leads to right ventricular hypertrophy, right ventricular enlargement, and finally to RVD. Hampole et al. investigated the relationship between RDW and mortality in 162 patients with PH, and found that RDW was independently associated with death in patients with PH, and that it performs better as a prognostic indicator than N-terminal pro-natriuretic peptide.12 A different study in COPD showed that high RDW levels were associated with RVD.17 In Dincer's study, 17.7 was established as the cut-off value for detecting RVD in COPD patients. In line with these studies, we concluded that high RDW is closely correlated with PH and RVD in COPD patients. Additionally, we found that an RDW level of 16.9 is highly sensitive and specific for the diagnosis of RVD, and that – by multivariate analysis – RVD was one of 2 factors influencing RDW levels in patients with COPD. We believe that high RDW value may be an indicator of RVD.

Smoking is the leading risk factor for COPD. It is also a major risk factor for the development of CVD.4 Smoking itself may cause systemic inflammation and, for example, increased total leukocyte count, but in COPD patients the degree of systemic inflammation is higher.18 Local inflammation is characterized by increased numbers of inflammatory cells, such as neutrophils, lymphocytes, and macrophages, and higher TNF-α and IL-8 concentrations in smokers than healthy controls.29 These results suggest that smoking may be associated with higher CRP production in the liver of subjects, and also with mechanisms related to systemic inflammation. A recent study19 exploring the association between smoking and RDW levels in healthy subjects showed that smoking raised RDW levels, and duration of smoking habit along with the number of pack-years correlated highly with RDW levels. In the present study, we detected a positive correlation between pack-years and RDW in healthy subjects. Additionally, RDW values were significantly higher in smokers compared to non-smokers. This finding suggests that systemic inflammation may also occur in healthy smokers who do not develop COPD. Therefore, we hypothesized that elevated RDW is associated with smoking, and may be a useful indicator of inflammatory activity in healthy smokers.

This study has some limitations: the sample size is small, and some correlations are weak. A longitudinal study to determine a causative relationship between systemic inflammation and CVD is needed to confirm our findings. This paper should be considered a pilot study needing a further validation step.

In conclusion, elevated RDW may be an indicator of underlying inflammation in COPD, and may in itself be a useful and simple tool to evaluating CVD and RVD in COPD patients. RDW was found to be more sensitive than CRP in predicting right ventricular dysfunction and cardiovascular disease in COPD patients. Additionally, measurement of RDW is more widely available and less expensive than measurement of other inflammatory cytokines (TNF-α, IL-8, etc.). RDW may also be a biomarker of systemic inflammation in smoking in healthy people.

Dr. ECS performed all the procedures, prepared the database and drafted the manuscript.

Dr. GO assisted Dr. ECS in performing the procedures, organized the database and contributed to the drafting of the manuscript.

Dr. MAO assisted Dr. ECS in performing the procedures and preparing the database.

The authors declare that they have no conflicts of interest.