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Abstract

Objectives:

We aimed to investigate the relationship between red cell distribution width (RDW) value and coronary collateral circulation (CCC) in patients with non-ST elevation myocardial infarction (NSTEMI).

Methods:

The study population consisted of 322 consecutive patients with NSTEMI. The patients were classified into impaired CCC (group 1, Rentrop grades 0-1) or good CCC (group 2, Rentrop grades 2-3). Baseline RDW was measured as part of the automated complete blood count.

Results:

The RDW values were significantly higher in patients with impaired CCC than in those with good CCC (17.2 ± 2.3 vs 14.5 ± 2.5, P < .001). In multivariate logistic regression analysis, RDW (odds ratio: 1.52, 95% confidence interval: 1.30-1.78, P < .001), baseline creatine kinase MB (CK-MB), and absence of preinfarction angina were found to be the independent predictors of impaired CCC. In receiver–operating characteristic curve analysis, the RDW value >15.5 yielded an area under curve value of 0.783, with 77% sensitivity and 73% specificity.

Conclusions:

Our study results demonstrated that, high RDW, high CK-MB, and absence of preinfarction angina were found to be independent predictors of impaired CCC.

Keywords

red cell distribution width coronary collateral circulation acute coronary syndrome

Introduction

Coronary collateral circulation (CCC) is an adaptive response to myocardial ischemia.¹ There are many collateral coronary arteries connecting the normal coronary arteries in individuals without angiographic coronary artery disease (CAD); however, most of these are not angiographically visible.^2,3 Patients with coronary stenosis or occlusion develop varying degrees of visible CCC. A well-developed CCC is associated with reduced infarction area and better ventricular functions.^4,5 Red cell distribution width (RDW) is a marker that has been shown to be correlated with adverse cardiovascular events, both in the short- and long term and associated with clinical conditions in various cardiovascular diseases.^6

–10 There is no study investigating the relationship between RDW and CCC to date. Therefore, in this study, we aimed to investigate the relationship between RDW value and CCC in patients with non-ST elevation myocardial infarction (NSTEMI).

Methods

Study Population

The study population consisted of 322 consecutive patients with NSTEMI who underwent coronary angiography at our hospital. The study was approved by the institutional ethics committee. The patients with baseline anemia (a hemoglobin level <13 g/dL in men and <12 g/dL in women; n = 32), history of blood transfusion within the last 3 months (n = 4), coronary angiogram showing a lesion of <80% stenosis (n = 66), active and ongoing infection (n = 12), chronic inflammatory disease (n = 4), and history of percutaneous coronary intervention (PCI; n = 17) or coronary artery bypass grafting (n = 11) were excluded from the study. Finally, 176 patients with NSTEMI were included in our study.

The clinical risk factors for the patients such as age, gender, hypertension (HTN), diabetes mellitus (DM), history of hyperlipidemia, smoking status, and family history were noted. Furthermore, on admission, each patient was evaluated for blood pressure, heart rate, Killip class, presence of cardiogenic shock, previously used drugs, presence of preinfarction angina, high sensitivity C-reactive protein (hs-CRP), serum creatinine, glucose, lipid profile, and hematologic indices. Prior to the PCI, each patient underwent transthoracic echocardiography using the biplane Simpson method and left ventricular ejection fraction (LVEF) was measured. Hematologic indices such as hemoglobin, white blood cell, RDW, mean platelet volume, and platelet counts were measured as part of the automated complete blood count (CBC) using a Coulter LH 780 Hematology Analyzer (Beckman Coulter Ireland Inc, Mervue, Galway, Ireland). Anemia on admission was defined as a baseline hemoglobin concentration less than 13 mg/dL in men and less than 12 mg/dL in women, in accordance with the World Health Organization criteria.¹¹ Hypertension was defined as systolic pressure >140 mm Hg and/or a diastolic pressure >90 mm Hg at least 2 times or if the individual was taking antihypertensive medications. The diagnosis of DM was based on the previous history of diabetes treated with or without drug therapies. Current smokers were defined as those who had smoked for some period during the past year.

Coronary Angiography

Quantitative coronary angiography was performed using standard Judkins method via transfemoral route. The inclusion criteria were the presence of 80% or greater degree of diameter stenosis in at least 1 coronary artery in coronary angiography. Therefore, since development of CCC is known to be inadequate in patients not complying with this criterium,¹² they were excluded from the study. The coronary collateral circulation was graded according to the Rentrop classification.¹² Accordingly, Grade 0 classified as no filling; Grade 1 classified as filling of side branches via collateral channels without visualization of the epicardial segment; Grade 2 classified as partial filling of the epicardial major coronary artery via collateral channels; and Grade 3 classified as complete filling of the epicardial major coronary artery. In patients with more than 1 coronary lesion, when there was more than 1 CCC, the CCC with the highest Rentrop grade was used. Thrombolysis in myocardial infarction (TIMI) flow grade and TIMI myocardial perfusion grade (TMPG) were measured as described before. The patients were classified into impaired CCC (group 1, Rentrop grades 0-1) or good CCC (group 2, Rentrop grades 2-3). Multivessel disease was defined as the presence of a lesion in 2 or more major epicardial arteries. Distal embolization was defined as distal filling defect with an abrupt “cutoff” in one or more peripheral coronary branch of interventional artery. Both TIMI flow grade and TMPG were measured as described before.^13,14

Statistical Analysis

Continuous variables are expressed as mean ± standard deviation whereas categorical variables are expressed as percentage. Comparisons between 2 CCC groups were made using the Student t test or Mann-Whitney U test or chi-square tests, as appropriate. Comparison between Rentrop grades were made using the analysis of variance and Tukey honestly significant difference test was chosen as a post hoc test. Multiple logistic regression analysis was performed to identify the independent predictors of CCC using variables showing marginal association with it on univariate testing (P < .10). Receiver–operating characteristic (ROC) analyses were used to detect the cutoff value of RDW in the prediction of CCC. Correlation analyses between variables were performed using Pearson or Spearman correlation. A P value <.05 was considered significant. All statistical analyses were carried out using SPSS 17.0 for Windows (SPSS Inc, Chicago, Illinois).

Results

A total of 176 patients with NSTEMI (mean age was 61.3 ± 12.3 years and male ratio was 57.4%) were included in the study. Table 1 shows the comparison of groups 1 and 2 relative to baseline characteristics. Compared to the patients with good CCC, patients with impaired CCC exhibited higher frequency of DM and lower preinfarction rates, as well as lower LVEF, higher neutrophil/lymphocyte ratio (NLR), hs-CRP, baseline creatine kinase MB (CK-MB) along with higher degree of impaired myocardial perfusion.

Table 1.

Baseline Characteristics According to Coronary Collateral Circulation.

Variables	Group 1 (n = 69)	Group 2 (n = 107)	P Value
Age, years	60.3 ± 12.7	61.9 ± 12.1	.421
Sex, male	58	57	.900
Diabetes, %	13	25.2	.051
Hypertension, %	49.3	41.1	.289
Smoking, %	53.6	57	.660
Family history of CAD, %	21.7	22.4	.914
Pre-infarction angina, %	44.9	22.4	.002
Killip status (≥II)	11.6	20.6	.124
Heart rate, 1/min	77 ± 13	80 ± 14	.228
Systolic blood pressure, mm Hg	134 ± 27	126 ± 33	.092
Diastolic blood pressure, mm Hg	79 ± 16	74 ± 21	.170
LVEF, %	49.6 ± 7.5	47.1 ± 8.7	.047
White blood cell count, ×10³ μL	9.0 ± 2.5	9.5 ± 2.9	.322
Platelet count, ×10³ μL	258 ± 46	259 ± 54	.897
Neutrophil/lymphocyte ratio	5.2 ± 2.9	6.7 ± 6.4	.034
Red cell distribution width	14.5 ± 2.5	17.2 ± 2.3	<.001
Mean platelet volume, fL	8.9 ± 1.1	9.0 ± 1.1	.970
Estimated GFR, mL/min per 1.73 m²	89 ± 19	87 ± 20	.573
Baseline troponin, µg/L	3.1 ± 3.9	4.1 ± 6.2	.269
Baseline CK-MB, IU/L	25 ± 15	37 ± 26	.001
LDL-Cholesterol, mg/dL	118 ± 43	115 ± 43	.735
HDL-Cholesterol, mg/dL	36.4 ± 12.2	36.7 ± 10.4	.898
Triglyceride, mg/dL	153 ± 120	134 ± 77	.212
hs-CRP, mg/L	4.5 ± 3.3	6.0 ± 6.1	.031
Previous medications, %
Aspirin	13	13.1	.994
Statin	21.7	21.5	.969
ACE-inhibitors/ARB	27.5	23.4	.702
β-Blocker	12.1	13	.861
CCB	4.3	8.4	.298
OAD	13	20.6	.202
Insulin	5.8	9.3	.397
Multivessel disease, %	56.5	48.6	.306
Postprocedural TIMI flow (≥III), %	91.3	83.6	.289
TMPG (≥II), %	85.5	74.8	.089
Distal embolization, %	0	3.7	.105

Abbreviations: CAD, coronary artery disease; LVEF, left ventricular ejection fraction; GFR, glomerular filtration rate; LDL, low-density lipoprotein; HDL, high-density lipoprotein; hs-CRP, high sensitivity C-reactive protein; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; OAD, oral antidiabetic drug; TIMI, thrombolysis in myocardial infarction; TMPG, TIMI myocardial perfusion grade. The bold values indicate univariate variables to entered in multivariate model, p < 0.10 .

Compared to the patients with good CCC, the patients with impaired CCC manifested significantly higher RDW values (17.2 ± 2.3 vs 14.5 ± 2.5, P < .001). Furthermore, Rentrop grade 2 and 3 patients had significantly lower RDW values when compared to the Rentrop grade 0 and 1 patients (13.3 ± 2.5, 14.8 ± 2.5, 16.6 ± 2.4, 18.2 ± 1.8, respectively, P value for trend <.001). Although RDW values were lower in Rentrop grade 1 patients than in Rentrop grade 0 patients (P = .004), there was no difference between Rentrop grade 2 and Rentrop grade 3 patients (P = .122; Figure 1).

Figure 1.

Red cell distribution width (RDW) value according to Rentrop grades.

Multivariate logistic regression test was employed for determining the independent predictors of impaired CCC. The variables that were found to have significance in the univariate analysis (pre-infarction angina, diabetes, LVEF, hs-CRP, NLR, RDW, baseline CK-MB, and TMPG) were included in the multivariate model. Among those, RDW (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.30-1.78, P < .001), baseline CK-MB (OR: 0.96, 95% CI: 0.93-0.99, P = .008), and presence of preinfarction angina (OR: 0.23, 95% CI: 0.10-0.54, P = .001) were found to be the independent predictors of impaired CCC (Table 2). The ROC curve analysis was performed to detect the best cutoff value of RDW in the prediction of impaired CCC. The RDW value >15.5 yielded an area under curve value of 0.783 (95% CI: 0.713-0.853; P < .001). Furthermore, RDW value >15.5 demonstrated a sensitivity of 77% and specificity of 73% for the prediction of CCC (Figure 2).

Table 2.

Multivariate Logistic Regression Analysis to Detect the Independent Predictors of Impaired Coronary Collateral Circulation.

Variables	Univariate OR (95% CI)	Univariate P Value	Multivariate OR, 95% CI	Multivariate P Value
Preinfarction angina	0.35 (0.15-0.68)	.002	0.23 (0.10-0.54)	.001
Diabetes	2.25 (0.98-5.13)	.051	2.21 (0.73-6.70)	.160
SBP	–	.092	0.99 (0.98-1.01)	.525
LVEF	–	.047	0.99 (0.93-1.05)	.837
Hs-CRP	–	.031	0.95 (0.86-1.05)	.363
Netrophil/lymphocyte ratio	–	.034	0.98 (0.88-1.10)	.771
Red cell distribution width	–	<.001	1.52 (1.30-1.78)	<.001
Baseline CK-MB	–	.001	0.96 (0.93-0.99)	.008
TMPG (≥II)	1.26 (0.99-1.61)	.089	1.03 (0.36-2.94)	.950

Abbreviations: OR, odds ratio; CI, confidence interval; SBP, systolic blood pressure; LVEF, left ventricular ejection fraction; hs-CRP, high sensitivity C-reactive protein; TMPG, TIMI myocardial perfusion grade.

Figure 2.

Receiver–operating characteristic (ROC) curves for red cell distribution width (RDW) value in prediction of impaired coronary collateral circulation (CCC).

Discussion

Our study results demonstrated that high RDW, high CK-MB, and absence of preinfarction angina were found to be independent predictors of impaired CCC.

Coronary collateral vessels are structures that are normally present in the human heart, though being invisible by angiography. However, when coronary stenosis develops, these normally invisible collaterals gradually become angiographically visible. The CCC development occurs as a result of angiogenesis (new vessel formation) and/or arteriogenesis (growth of preexisting arterioles).¹⁵ Many factors may take part in the development of CCC such as severity and rate of progression of coronary stenosis, DM, HTN, smoking status, endothelial dysfunction, exercise, endogenous mediators, oxidative stress, and drugs used.¹ The CCC development in acute coronary syndromes has been found to be associated with better myocardial perfusion and ventricular functions as well as lower incidence of adverse cardiovascular events in the long term.^16
–18

In CCC development, many endogenous mediators such as growth factors, vascular endothelial growth factor (VEGF), nitric oxide (NO), inflammatory markers, and neurohumoral markers are involved along with endothelial dysfunction.¹⁵ The RDW is a marker of variation in size of circulating red cells and is routinely reported by red blood cell analyzers as a part of routine CBC. Many studies have shown that RDW is an independent predictor of adverse events in the long term in both stable and acute coronary syndromes and that it is associated with impaired epicardial and myocardial perfusion after PCI in cases of acute coronary syndromes.^7,19 However, to date no study has been performed on the relationship between RDW and development of CCC in patients with CAD. In the present study, we demonstrated that raised RDW level was an independent predictor of impaired CCC. The mechanistic relationship between RDW and CCC can be explained by 3 proposed mechanisms. First, elevated RDW levels may inhibit the development of CCC. Raised RDW levels are associated with high erythropoietin,²⁰ B-type natriuretic peptide (BNP),²¹ and tumor necrosis factor α (TNF-α)²² levels. Furthermore, independent of RDW, these factors are also at raised levels in acute coronary syndrome as well. Pedram et al showed that natriuretic peptides inhibited angiogenesis.²³ Erythropoietin and TNF-α modulate erythropoiesis as well. Second, the developmental process of CCC may end up with increased RDW. Some endogenous factors that are increased throughout the development of CCC may alter RDW levels by affecting erythropoiesis. Several important angiogenesis modulators such as VEGF, fibroblast growth factor (FGF), and platelet-derived growth factor can also further activate erythropoiesis by increasing erythropoietin synthesis.^24
–26 Third, other than causal relationship, the process modulating the development of CCC may also have an impact on the RDW levels. For instance, endothelial dysfunction is important in terms of CCC development; however, it is known to be associated with RDW levels²⁷ as well. Furthermore, in the present study, we also found a relationship between CCC and preinfarction angina. It is known that well-developed CCC was observed in the presence of preinfarction angina.¹

In conclusion, whether it is the cause or the result, it is a fact that RDW levels are associated with impaired development of CCC in patients with NSTEMI. This suggests that clinically determining the RDW levels, which requires only a simple and cheap test, can be helpful in the detection of high-risk patients.

Limitation

Relatively small sample size is one of the major limitations of our study. The cross-sectional design of our study makes it difficult to comment on the causal relationship of RDW and impaired CCC. Finally, one of the most important limitations was the failure to measure some parameters such as FGF, VEGF, NO, erythropoietin, TNF-α, and BNP that could be helpful in evaluating the relationship between RDW and impaired CCC in detail.

Conclusion

In conclusion, we demonstrated that higher RDW value was associated with impaired CCC in patients with NSTEMI. We need further studies to investigate the cause and effect relationship between RDW and CCC.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Celik

Iyisoy

[Coronary collateral circulation]. Turk Kardiyol Dern Ars. 2010;38(7):505–514.

Levin

. Pathways and functional significance of the coronary collateral circulation. Circulation. 1974;50(4):831–837.

Elayda

Mathur

Hall

Massumi

Garcia

de Castro

. Collateral circulation in coronary artery disease. Am J Cardiol. 1985;55(1):58–60.

Hirai

Fujita

Sasayama

. Importance of coronary collateral circulation for kinetics of serum creatine kinase in acute myocardial infarction. Am J Cardiol. 1987;60(7):446–450.

Kodama

Kusuoka

Sakai

. Collateral channels that develop after an acute myocardial infarction prevent subsequent left ventricular dilation. J Am Coll Cardiol. 1996;27(5):1133–1139.

Azab

Torbey

Hatoum

. Usefulness of red cell distribution width in predicting all-cause long-term mortality after non-ST-elevation myocardial infarction. Cardiology. 2011;119(2):72–80.

Isik

Kurt

Ayhan

Tanboga

Ergelen

Uyarel

. The impact of admission red cell distribution width on the development of poor myocardial perfusion after primary percutaneous intervention. Atherosclerosis. 2012;224(1):143–149.

Karabulut

Uzunlar

. Correlation between red cell distribution width and coronary ectasia in the acute myocardial infarction. Clin Appl Thromb Hemost. 2012;18(5):551–552.

Isik

Kurt

Ayhan

. Relation of red cell distribution width with presence and severity of coronary artery ectasia. Clin Appl Thromb Hemost. 2012;18(5):441–447.

10.

Dogdu

Koc

Kalay

. Assessment of red cell distribution width (RDW) in patients with coronary artery ectasia. Clin Appl Thromb Hemost. 2012;18(2):211–214.

11.

World Health Organization. Indicators and Strategies for Iron Deficiency and Anemia Programmes. Report of the WHO/UNICEF/UNU Consultation. Geneva, Switzerland: World Health Organization; 1993.

12.

Rentrop

Thornton

Feit

Van Buskirk

. Determinants and protective potential of coronary arterial collaterals as assessed by an angioplasty model. Am J Cardiol. 1988;61(10):677–684.

13.

The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group. N Engl J Med. 1985;312(14):932–936.

14.

Gibson

Cannon

Murphy

. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation. 2000;101(2):125–130.

15.

Seiler

. The Collateral Circulation of the Heart. London: Springer; 2009:418.

16.

McMurtry

Lewin

Knudtson

. The clinical profile and outcomes associated with coronary collaterals in patients with coronary artery disease. Can J Cardiol. 2011;27(5):581–588.

17.

Ilia

Wolak

Amit

Weinstein

. Collateral blood flow can predict myocardial blush grade in primary coronary intervention. Catheter Cardiovasc Interv. 2012;80(1):67–70.

18.

Nathoe

Koerselman

Buskens

. Determinants and prognostic significance of collaterals in patients undergoing coronary revascularization. Am J Cardiol. 2006;98(1):31–35.

19.

Isik

Uyarel

Tanboga

. Relation of red cell distribution width with the presence, severity, and complexity of coronary artery disease. Coron Artery Dis. 2012;23(1):51–56.

20.

Kario

Matsuo

Kodama

Asada

. Clinical significance of red blood cell distribution width in the elderly: a potential indicator of bone marrow stimulation by erythropoietin. Int J Lab Hematol. 1993;15(3):185–193.

21.

Fukuta

Ohte

Mukai

. Elevated plasma levels of B-type natriuretic peptide but not C-reactive protein are associated with higher red cell distribution width in patients with coronary artery disease. Int Heart J. 2009;50(3):301–312.

22.

Forhecz

Gombos

Borgulya

Pozsonyi

Prohaszka

Janoskuti

. Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. Am Heart J. 2009;158(4):659–666.

23.

Pedram

Razandi

Levin

. Natriuretic peptides suppress vascular endothelial cell growth factor signaling to angiogenesis. Endocrinology. 2001;142(4):1578–1586.

24.

Tam

Wei

Rudge

. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med. 2006;12(7):793–800.

25.

Koritschoner

Bartunek

Knespel

Blendinger

Zenke

. The fibroblast growth factor receptor FGFR-4 acts as a ligand dependent modulator of erythroid cell proliferation. Oncogene. 1999;18(43):5904–5914.

26.

Dainiak

Davies

Kalmanti

Lawler

Kulkarni

. Platelet-derived growth factor promotes proliferation of erythropoietic progenitor cells in vitro. J Clin Invest. 1983;71(5):1206–1214.

27.

Afonso

Zalawadiya

Veeranna

Panaich

Niraj

Jacob

. Relationship between red cell distribution width and microalbuminuria: a population-based study of multiethnic representative US adults. Nephron Clin Pract. 2011;119(4):c277–c282.

Relation of Coronary Collateral Circulation With Red Cell Distribution Width in Patients With Non-ST Elevation Myocardial Infarction

Abstract

Objectives:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Study Population

Coronary Angiography

Statistical Analysis

Results

Discussion

Limitation

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

References