Despite advances in diagnosis and treatment, ST-segment elevation myocardial infarction (STEMI) remains the most common cause of cardiovascular mortality and morbidity in both developing and developed countries. It is crucial to identify high-risk patients who will require immediate and intensive treatment for myocardial infarction (MI).1,2

Thrombosis and inflammation play an important role not only in the pathophysiology of acute ischemic syndromes,3 but also in the process of atherogenesis, especially in the progression of disease.4 Red cell distribution width (RDW) is a measure of variation in the size of circulating red blood cells and is routinely reported as part of an automated full blood count.5 Recent studies have reported a strong independent relation between elevated RDW and short- and long-term prognosis in various disorders such as coronary artery disease (CAD),6 peripheral vascular disease,7 MI,8 acute and chronic heart failure9,10 and pulmonary embolism,11 as well as in the general population.12 A correlation between RDW and the complexity and severity of CAD has been presented in a previous study.13

Both chronic inflammation and neurohumoral activation lead to an increase in the heterogeneity of circulating erythrocytes, resulting in elevated RDW.14,15

Platelets play a crucial role in the pathogenesis of acute coronary syndrome (ACS). Activated platelets adhere to the vessel wall at the site of ruptured plaque, and initiate arterial thrombus formation, which leads to ischemia or infarction.16,17 Platelets both release markers of inflammation such as soluble CD40 ligand and beta-thromboglobulin18,19 and directly stimulate other cells (including leukocytes, lymphocytes, and monocytes), which can lead to further release of inflammatory markers.20,21 A decreased platelet count was found to be associated with increased infarct size and extent, mean platelet volume and increased platelet aggregation in ACS in previous studies.22–24 There is controversy in the literature concerning the relation between platelet count and short- and long-term mortality in MI.25–28 Although RDW has been related to elevated risk of adverse clinical outcomes in MI, to the best of our knowledge no study has examined the relation between RDW-to-platelet ratio (RPR) and in-hospital and long-term prognosis in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).

The aim of the present study was to investigate the relationship between admission RPR and in-hospital and long-term prognosis in terms of cardiovascular mortality and major adverse cardiovascular events (MACE) in patients with STEMI undergoing primary PCI.

We studied 470 of 530 patients who presented with STEMI and underwent primary PCI during the study period. Of these 470 patients (374 men, 96 women), 316 were in the low RPR group and 154 were in the high RPR group. Baseline demographic and clinical characteristics of the patients according to RPR groups are summarized in Table 1. The mean RPR of the study population was 0.057 (range: 0.021–0.195). The high RPR group were older (p=0.01) and tended to have a higher frequency of hypertension (p=0.018) than the low RPR group. Male gender, family history of CAD, diabetes, hyperlipidemia, smoking, previous history of CABG, PCI or MI, anterior MI, Killip class, reperfusion time and door-to-balloon time and ejection fraction were not statistically different between the two groups. Patients’ laboratory characteristics on admission according to RPR group are presented in Table 2. Total and LDL cholesterol levels were found to be significantly lower in the high RPR group than in the low RPR group (p<0.001 for both). Basal creatinine, hematocrit, peak CK-MB, peak troponin, HDL cholesterol, triglyceride, blood glucose, and white blood cell count were not statistically different between the groups. As expected, the high RPR group had significantly higher RDW and lower platelet count (p<0.001 for both).

The comparison of angiographic and procedural characteristics between the high and low RPR groups is reported in Table 3. There was no difference between the groups in terms of culprit lesion, number of diseased vessels, procedural success rate, pre-procedural TIMI flow, post-procedural TIMI flow, stent length, stent diameter, primary balloon angioplasty (PBA), stent implantation, PCBA and stent implantation, or use of drug-eluting stents (DES) (all p>0.05). At the time of hospital discharge, the duration of dual antiplatelet therapy after PCI and the use of other cardiac medications including ACEIs, beta-blockers and statins were similar between the groups.

The comparison between high and low RPR groups in terms of in-hospital adverse outcomes after PCI is presented in Table 4. The rate of in-hospital cardiovascular mortality in patients with high RPR was nearly three times that of those with low RPR (9.3 vs. 3.2%, p<0.006). The MACE rate was significantly higher in patients with high RPR than in those with low RPR (14.3 vs. 8.9%, p=0.007). Furthermore, cardiopulmonary resuscitation (p=0.026), advanced heart failure (p=0.022), cardiogenic shock (p=0.018) and inotrope use (p=0.018) were more frequent in the high RPR group.

One-year MACE are reported in Table 5. All-cause mortality was significantly higher in the high RPR group compared to the low RPR group (p=0.007). During the course of the study (mean follow-up of 12 months), 41 deaths from cardiac causes occurred out of 470 patients (8.7%). The distribution of causes of cardiovascular mortality were as follows: four patients with unexplained sudden death, 15 with myocardial infarction, 14 with decompensated heart failure, and eight with hemodynamically significant arrhythmia. Cardiovascular mortality was significantly higher in the high RPR group (n=22) than in the low RPR group (n=19) (14.3% vs. 6%; p<0.003). The Kaplan–Meier survival plot for one-year cardiovascular mortality in both groups is presented in Figure 1. Also, the high RPR group had a trend toward a higher incidence of MACE (p=0.034), fatal reinfarction (p=0.008), cardiac rehospitalization (p=0.015), and advanced heart failure (p=0.034). Rates of other complications were not statistically different between the groups.

Figure 1.

Kaplan–Meier curve for long-term survival according to red cell distribution width-to-platelet ratio (RPR) with a cutoff of 0.061. Cumulative event-free survival was defined as freedom from death.

(0,08MB).

The independent predictors for one-year cardiovascular mortality, including age, male gender, hypertension, RDW, no-reflow, diabetes, hypertension, anterior MI, Killip class >1, platelet count, LVEF, and RPR were included in a Cox proportional hazard model and analyzed in a stepwise fashion. In multivariate analysis, RPR >0.061 (hazard ratio [HR] 3.106, 95% confidence interval [CI] 1.456–6.623, p=0.003), age (HR 1.044, 95% CI 1.012–1.078, p=0.007), no-reflow (HR 2.331, 95% CI 1.094–4.968, p=0.028), Killip class >1 (HR 2.886, 95% CI 1.254–6.643, p=0.013), and LVEF (HR 0.891, 95% CI 0.853–0.931, p<0.001) were significant independent predictors of one-year cardiovascular mortality after adjustment for other risk factors such as diabetes, hypertension, anterior MI and platelet count which had been found to be significant predictors of one-year cardiovascular mortality in univariate analysis (Table 6).

The main findings of the present study were as follows: (1) the rate of in-hospital cardiovascular mortality was nearly three times higher in the RPR group than in the low RPR group; (2) the rates of in-hospital and one-year MACE were significantly higher in patients with high RPR than in those with low RPR; (3) one-year all-cause mortality was significantly higher in the high RPR group compared to the low RPR group; (4) one-year cardiovascular mortality was significantly higher in the high RPR group; and (5) in multivariate analysis, RPR >0.061, age, no-reflow, Killip class >1, and LVEF were found to be significant independent predictors of one-year cardiovascular mortality after adjustment for other risk factors.

To the best of our knowledge, this is the first study to demonstrate the relationship between RPR and in-hospital and long-term prognosis in terms of cardiovascular mortality and MACE in patients with STEMI undergoing primary PCI.

RDW is a good indicator of variation in the size of circulating erythrocytes and can easily be measured by routine analysis of the complete blood count. Increased RDW reflects the heterogeneity of cell sizes in the peripheral blood smear.32 The most common conditions reported in recent studies in which elevated RDW is seen include ineffective red cell production (due to iron deficiency, vitamin B12 or folate deficiency, hemoglobinopathies, and renal dysfunction), increased red cell destruction (such as hemolysis), blood transfusion, thrombotic thrombocytopenic purpura, inflammatory bowel disease and pregnancy.33–35

The prognostic significance of admission RDW has been reported by Uyarel et al. in patients with non-ST-segment elevation myocardial infarction (NSTEMI) undergoing primary PCI. This study demonstrated that higher baseline RDW was associated with elevated risk of in-hospital and long-term cardiovascular mortality and longer hospital stay.36 RDW was also found to be an important independent predictor of all-cause long-term mortality in NSTEMI.14 Moreover, a graded positive independent relation between admission and discharge RDW values and risk of all-cause mortality and development of new-onset heart failure was found in patients with MI in a study by Dabbah et al.7 A raised baseline RDW was found to be independently associated with abnormal reperfusion and increased risk of in-hospital and long-term cardiovascular mortality in STEMI patients undergoing primary PCI.37 In another study, a significant independent association was demonstrated between RDW and the presence and severity of CAD as assessed by the SYNTAX score.38 The prognostic value of RDW regarding MACE was reported in different large populations with heart failure in previous studies.9 In addition, raised RDW was identified as a strong independent predictor of all-cause mortality in an unselected population of male patients referred for coronary angiography in a study by Cavusoglu et al.39 The relation of RDW with all-cause mortality has been assessed not only in various diseases, but also in healthy subjects. Patel et al. found that for every 1% increment in RDW, the all-cause mortality risk increased by 22%.12 In our study, the in-hospital and long-term prognostic value of RPR was investigated in patients with STEMI undergoing primary PCI. In-hospital cardiovascular mortality, one-year all-cause mortality and one-year cardiovascular mortality were all found to be significantly higher in the high RPR group, in agreement with previous studies. Also, the rates of in-hospital and one-year MACE were higher in the high RPR group, similar to some previous studies.

The reasons for the relationship between RDW and MACE in STEMI are unclear. The main possible mechanisms include inflammatory and neurohormonal activation, which have a crucial role in the initiation and progression of the atherosclerotic process, resulting in CAD and MI.40 Elevated RDW has been reported as a marker of severe inflammation in previous studies.41,42 Lippi et al. showed a relationship between generalized inflammation and increased levels of RDW. They also demonstrated an association between RDW and high-sensitivity C-reactive protein and erythrocyte sedimentation rate, which are reliable indicators of inflammation.43 Inflammation might contribute to increased RDW by inhibiting erythropoietin-induced erythrocyte maturation and impairing iron metabolism.44,45 Furthermore, raised RDW may reflect the production of humoral mediators by bone marrow. In the early phase of acute STEMI, infarction-related inflammatory cytokines and neurohumoral mediators are activated and plasma erythropoietin levels increase. These changes ultimately pave the way for an increase in the heterogeneity of circulating erythrocytes.46,47 Neurohumoral activation may also accelerate erythropoiesis.48

It has been reported that humoral mediators contribute to major adverse clinical events through different mechanisms.49 The renin-angiotensin system, via angiotensin II, may affect erythropoiesis by regulating erythropoietin levels and through direct stimulation of erythroid progenitor cells.48 Furthermore, adrenergic activation may elicit a bone marrow response and increase erythropoietin levels independently of hemoglobin levels in patients with STEMI.47 Increased RDW has been reported to be associated with early signs of subclinical atherosclerosis such as elevated intima-media thickness and incidence of carotid plaque.50 In our study, hypertension was observed more in the high RPR group, which supports the positive relation of increased RDW with severity of inflammation and oxidative stress. However, total and LDL cholesterol were lower in the high RPR group, similar to the results of Uyarel et al.’s study.36

Platelets play an important role in the pathogenesis of ACS. A decreased platelet count was found to be associated with increased infarct size and extent, mean platelet volume and platelet aggregation in MI in previous studies.22–24 Fagher et al. demonstrated that mean platelet count was significantly lower in patients with MI as compared to healthy controls and patients with peripheral arterial disease. The changes in platelet count during MI seemed to parallel the changes in platelet function.22 Also, Pizzulli et al. demonstrated that platelet count was lower in patients with unstable angina pectoris compared to stable CAD after coronary angiography. In this study, patients with unstable angina requiring immediate PCI had an even lower platelet count and higher mean platelet volume than the rest of the population with unstable angina.24 In our study, the high RPR group had significantly lower platelet count compared to the low RPR group. This may be associated with or preceded by a systemic increase in platelet destruction rate in MI that is not completely compensated for by an increase in platelet production rate. Moreover, platelet consumption at the site of the culprit lesion may contribute to thrombus formation in MI and thus to a further increase in platelet destruction. The combination of increased RDW and decreased platelet count, as seen in the high RPR group, predicted in-hospital and long-term prognosis of STEMI treated by primary PCI in our study. Similarly to our study results, platelet count was found to be lower in high burden thrombus formation than in low burden thrombus formation in STEMI patients undergoing primary PCI in a study by Yusuf et al.51

There are conflicting results in the literature in terms of the relation between admission platelet count and cardiovascular mortality and MACE in ACS. Mueller et al. reported an association between low platelet count and cardiovascular mortality in NSTEMI. However, Azab et al. did not demonstrate an independent relation between platelet count and cardiovascular mortality.14,25 In our study, in agreement with previous publications, there was no relation between admission platelet count and in-hospital and long-term prognosis in STEMI patients undergoing primary PCI. RPR was found to be a more powerful predictor of in-hospital and long-term prognosis in STEMI than RDW or platelet count alone. Moreover, RPR was shown to be a significant independent predictor of one-year cardiovascular mortality after adjustment for other risk parameters.

The present study has some limitations. First, it was performed in a single center and is thus subject to selection bias. Second, we only measured Hb levels, not other factors which affect RDW such as iron, vitamin B12, and folate. Third, even though we speculate that neurohumoral activation may be an important link between increased RDW and adverse outcomes in CAD, we did not measure inflammatory and neurohumoral markers including C-reactive protein, brain natriuretic peptide, other proinflammatory cytokines, norepinephrine, or angiotensin II. Fourth, we could not evaluate changes in RPR in response to aggressive treatment due to lack of serial measurements of RDW and platelet count.

We demonstrate that higher RPR is associated with an increased risk for in-hospital and long-term MACE, all-cause mortality and cardiovascular mortality in STEMI patients undergoing primary PCI. RPR is an inexpensive and readily available biomarker that provides an additional level of risk stratification beyond that provided by conventional risk parameters in predicting long-term MACE and cardiovascular mortality in STEMI patients undergoing primary PCI.

The authors have no conflicts of interest to declare.