Abstract
OBJECTIVE:
An elevated red cell distribution width has been recognized as a predictor of various cardiovascular diseases. Slow coronary flow syndrome is an important angiographic clinical entity with an unknown etiology. This study aimed to examine the relationship between red cell distribution width and the presence of slow coronary flow syndrome.
METHODS:
In total, 185 patients with slow coronary flow syndrome and 183 age- and gender-matched subjects with normal coronary flow (controls) were prospectively enrolled in this study. Red cell distribution width and C-reactive protein were measured upon admission, and the results were compared between the patients with slow coronary flow syndrome and normal controls.
RESULTS:
Red cell distribution width levels were significantly higher in the patients with slow coronary flow syndrome than the normal controls. Moreover, the data showed that the plasma C-reactive protein levels were also higher in the patients with slow coronary flow syndrome than in the normal controls. In addition, a multivariate analysis indicated that C-reactive protein and red cell distribution width were the independent variables most strongly associated with slow coronary flow syndrome. Finally, the red cell distribution width was positively correlated with C-reactive protein and mean thrombosis in the myocardial infarction frame counts of the patients with slow coronary flow syndrome.
CONCLUSION:
The data demonstrated that red cell distribution width levels are significantly higher and strongly positively correlated with both C-reactive protein and thrombosis in the myocardial infarction frame counts of patients with slow coronary flow syndrome. These findings suggest that red cell distribution width may be a useful marker for patients with slow coronary flow syndrome.
Red Cell Distribution Width; Slow Coronary Flow Syndrome; C-Reactive Protein; Biomarker; Inflammation
INTRODUCTION
Slow coronary flow syndrome (SCFS) is an angiographic observation characterized by
angiographically normal or near-normal coronary arteries with the delayed progression of contrast
dye injected into the coronary tree (11. Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow
velocity of dye in coronary arteries-a new angiographic finding. Am Heart J. 1972;84(1):66-71,
http://dx.doi.org/10.1016/0002-8703(72)90307-9.
http://dx.doi.org/10.1016/0002-8703(72)9...
2. Beltrame JF, Limaye SB, Wuttke RD, Horowitz JD. Coronary hemodynamic and
metabolic studies of the coronary slow flow phenomenon. Am Heart J. 2003;146(1):84-90,
http://dx.doi.org/10.1016/S0002-8703(03)00124-8.
http://dx.doi.org/10.1016/S0002-8703(03)...
-33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
). Despite the relatively good prognosis of SCFS patients, the chronic nature of
the persistent chest discomfort can significantly impair quality of life (11. Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow
velocity of dye in coronary arteries-a new angiographic finding. Am Heart J. 1972;84(1):66-71,
http://dx.doi.org/10.1016/0002-8703(72)90307-9.
http://dx.doi.org/10.1016/0002-8703(72)9...
). In addition, many SCFS patients suffer from recurrent chest pain, resulting in
emergency room evaluations, hospitalizations, and repeat cardiac catheterizations, according to a
previous study (22. Beltrame JF, Limaye SB, Wuttke RD, Horowitz JD. Coronary hemodynamic and
metabolic studies of the coronary slow flow phenomenon. Am Heart J. 2003;146(1):84-90,
http://dx.doi.org/10.1016/S0002-8703(03)00124-8.
http://dx.doi.org/10.1016/S0002-8703(03)...
). More importantly, life threatening
arrhythmias and sudden cardiac death have also been reported in these patients (33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
). Although intensive studies have been performed over the past
several decades, the underlying mechanism responsible for SCFS remains unknown (11. Tambe AA, Demany MA, Zimmerman HA, Mascarenhas E. Angina pectoris and slow flow
velocity of dye in coronary arteries-a new angiographic finding. Am Heart J. 1972;84(1):66-71,
http://dx.doi.org/10.1016/0002-8703(72)90307-9.
http://dx.doi.org/10.1016/0002-8703(72)9...
2. Beltrame JF, Limaye SB, Wuttke RD, Horowitz JD. Coronary hemodynamic and
metabolic studies of the coronary slow flow phenomenon. Am Heart J. 2003;146(1):84-90,
http://dx.doi.org/10.1016/S0002-8703(03)00124-8.
http://dx.doi.org/10.1016/S0002-8703(03)...
-33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
).
Red cell distribution width (RDW), a part of a routine complete blood count, measures the
variability in the size of circulating erythrocytes, which has been utilized in the differential
diagnosis of anemia (44. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, et al. Red cell
distribution width as a novel prognostic marker in heart failure: data from the CHARM program and
the Duke database. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
,55. Lappe JM, Home BD, Shah SH, May HT, Muhlestein JB, Lappe DL, et al. Red cell
distribution widtd, C-reactive protein, the complete blood count, and mortality in patients with
coronary disease and a normal comparison polpulation. Clin Chim Acta. 2011;412(23-24):2094-9,
http://dx.doi.org/10.1016/j.cca.2011.07.018.
http://dx.doi.org/10.1016/j.cca.2011.07....
). Recently, elevated RDW levels have been suggested as a readily available marker for and
independent predictor of various cardiovascular diseases, including acute and chronic arterial
diseases (66. Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell
distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol.
2010;105(3):312-7, http://dx.doi.org/10.1016/j.amjcard.2009.09.027.
http://dx.doi.org/10.1016/j.amjcard.2009...
7. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Cholesterol and
Recurrent Events Trial Investigators. Relation between red blood cell distribution width and
cardiovascular event rate in peoples with coronary disease. Circulation. 2008;117(2):163-8,
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727545.
http://dx.doi.org/10.1161/CIRCULATIONAHA...
8. Ye Z, Smith C, Kullo IJ. Usefulness of red cell distribution width to predict
mortality in patients with peripheral artery disease. Am J Cardiol. 2011;107(8):1241-5,
http://dx.doi.org/10.1016/j.amjcard.2010.12.023.
http://dx.doi.org/10.1016/j.amjcard.2010...
9. Dogdu O, Koc F, Kalay N, Yarliglues M, Elicik D, karayakali M, Ozbek K, Kaya MG.
Assessment of red cell distribution width (RDW) in patients with coronary artery ectasia. Clin Appl
Thromb Hemost. 2012;18(2):211-214, http://dx.doi.org/10.1177/1076029611418964.
http://dx.doi.org/10.1177/10760296114189...
-1010. Ani C, Ovbiagele B. Elevated red blood cell distribution width to predicts
mortality in persons with known stroke. J Neurol Sci. 2009;277(1-2):103-8,
http://dx.doi.org/10.1016/j.jns.2008.10.024.
http://dx.doi.org/10.1016/j.jns.2008.10....
),
percutaneous coronary intervention after acute myocardial infarction (1111. Karabulut A, Uyarel H, Uzunlar B, Cakmak M. Elevated red cell distribution level
predicts worse postinterventional thrombosis in myocardial infarction flow reflecting abnormal
reperfusion in acute myocardial infarction treated with a primary coronary intervention. Coron
Artery Dis. 2012;23(1):68-72, http://dx.doi.org/10.1097/MCA.0b013e32834f1188.
http://dx.doi.org/10.1097/MCA.0b013e3283...
,1212. Lsik T, Kurt M, Ayhan E, Tanboga IH, Ergelen M, Uyarel H. The impact of
admission red cell distribution width on the development of poor myocardial perfusion after primary
percutaneous intervention. Atherosclerosis. 2012;224(1):143-9.), and heart failure (1313. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJV, Pfeffer MA, et al. Red
cell distribution width as a novel prognostic marker in heart failure - Data from the CHARM program
and the Duke Databank. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
,1414. Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, et al. Validation
and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.
J Cardial Fail. 2010;16(3):230-8,
http://dx.doi.org/10.1016/j.cardfail.2009.11.003.
http://dx.doi.org/10.1016/j.cardfail.200...
) in the elderly and
general populations (1515. Patel KV, Semba RD, Ferrucci L, Newman AB, Fried LP, Wallace RB, et al. Red cell
distribution width and mortality in older adults: a meta-analysis. J Gerontol A Biol
Sci Med Sci. 2010;65(3):258-65, http://dx.doi.org/10.1093/gerona/glp163.
http://dx.doi.org/10.1093/gerona/glp163...
,1616. Peristein TS, Weuve J, Pfeffer MA, Beckman JA. Red blood cell distribution width
and mortality risk in a community-based prospective cohort. Arch Intern Med. 2009;169(6):588-94,
http://dx.doi.org/10.1001/archinternmed.2009.55.
http://dx.doi.org/10.1001/archinternmed....
).
It has been reported that inflammation may be a potential mechanism underlying elevated RDW
levels in patients with chronic and acute cardiovascular diseases (66. Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell
distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol.
2010;105(3):312-7, http://dx.doi.org/10.1016/j.amjcard.2009.09.027.
http://dx.doi.org/10.1016/j.amjcard.2009...
7. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Cholesterol and
Recurrent Events Trial Investigators. Relation between red blood cell distribution width and
cardiovascular event rate in peoples with coronary disease. Circulation. 2008;117(2):163-8,
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727545.
http://dx.doi.org/10.1161/CIRCULATIONAHA...
8. Ye Z, Smith C, Kullo IJ. Usefulness of red cell distribution width to predict
mortality in patients with peripheral artery disease. Am J Cardiol. 2011;107(8):1241-5,
http://dx.doi.org/10.1016/j.amjcard.2010.12.023.
http://dx.doi.org/10.1016/j.amjcard.2010...
9. Dogdu O, Koc F, Kalay N, Yarliglues M, Elicik D, karayakali M, Ozbek K, Kaya MG.
Assessment of red cell distribution width (RDW) in patients with coronary artery ectasia. Clin Appl
Thromb Hemost. 2012;18(2):211-214, http://dx.doi.org/10.1177/1076029611418964.
http://dx.doi.org/10.1177/10760296114189...
10. Ani C, Ovbiagele B. Elevated red blood cell distribution width to predicts
mortality in persons with known stroke. J Neurol Sci. 2009;277(1-2):103-8,
http://dx.doi.org/10.1016/j.jns.2008.10.024.
http://dx.doi.org/10.1016/j.jns.2008.10....
11. Karabulut A, Uyarel H, Uzunlar B, Cakmak M. Elevated red cell distribution level
predicts worse postinterventional thrombosis in myocardial infarction flow reflecting abnormal
reperfusion in acute myocardial infarction treated with a primary coronary intervention. Coron
Artery Dis. 2012;23(1):68-72, http://dx.doi.org/10.1097/MCA.0b013e32834f1188.
http://dx.doi.org/10.1097/MCA.0b013e3283...
12. Lsik T, Kurt M, Ayhan E, Tanboga IH, Ergelen M, Uyarel H. The impact of
admission red cell distribution width on the development of poor myocardial perfusion after primary
percutaneous intervention. Atherosclerosis. 2012;224(1):143-9.
13. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJV, Pfeffer MA, et al. Red
cell distribution width as a novel prognostic marker in heart failure - Data from the CHARM program
and the Duke Databank. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
-1414. Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, et al. Validation
and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.
J Cardial Fail. 2010;16(3):230-8,
http://dx.doi.org/10.1016/j.cardfail.2009.11.003.
http://dx.doi.org/10.1016/j.cardfail.200...
). Additionally, emerging data have suggested
that inflammation may play a role in the pathogenesis of SCFS (33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
). Accordingly, we hypothesized that an elevated RDW level might be significantly
associated with the presence of SCFS because of the inflammatory features of this unique disorder.
Therefore, in the present study, we prospectively examined the relationship between RDW levels and
the presence of SCFS.
METHODS
Subjects
This observational study was derived from a cohort of patients prospectively entered into a database. The purpose was to assess the prognostic significance of various plasma biomarkers in patients with known or suspected coronary artery disease in our divisions at the Fu Wai and Anzhen Hospitals Beijing. The study was approved by the local ethics committee and complied with the Declaration of Helsinki. The study population was selected between December 2009 and March 2012 based on the presence of angina-like chest pain or a positive treadmill exercise test. Finally, 185 consecutive SCFS patients and 183 age- and gender-matched normal controls were enrolled. The inclusion criteria were patients with angiographically proven normal coronary arteries and slow flow in at least one of three main coronary arteries (SCFS group, 159 males and 26 females, mean age 46±10 years), and 183 subjects with angiographically proven normal coronary arteries with normal coronary flow ([NCF] group, 162 males and 21 females, mean age 44±8 years) were also included.
All subjects enrolled in this study had normal hepatic and renal function. Current smoking,
hypertension, diabetes mellitus, and hyperlipidemia were defined according to past literature
reports (44. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, et al. Red cell
distribution width as a novel prognostic marker in heart failure: data from the CHARM program and
the Duke database. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
5. Lappe JM, Home BD, Shah SH, May HT, Muhlestein JB, Lappe DL, et al. Red cell
distribution widtd, C-reactive protein, the complete blood count, and mortality in patients with
coronary disease and a normal comparison polpulation. Clin Chim Acta. 2011;412(23-24):2094-9,
http://dx.doi.org/10.1016/j.cca.2011.07.018.
http://dx.doi.org/10.1016/j.cca.2011.07....
6. Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell
distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol.
2010;105(3):312-7, http://dx.doi.org/10.1016/j.amjcard.2009.09.027.
http://dx.doi.org/10.1016/j.amjcard.2009...
-77. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Cholesterol and
Recurrent Events Trial Investigators. Relation between red blood cell distribution width and
cardiovascular event rate in peoples with coronary disease. Circulation. 2008;117(2):163-8,
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727545.
http://dx.doi.org/10.1161/CIRCULATIONAHA...
). The
following exclusion criteria were applied: evidence of coronary artery disease, myocardial
infarction, valvular heart disease, congestive heart failure, left ventricular dysfunction, and
echocardiographically proven left ventricular hypertrophy, or a history of dysphagia, swallowing and
intestinal motility disorders, untreated thyroid disease, sinus node dysfunction or conduction
disturbance, estrogen replacement therapy, carcinoma, poorly controlled hypertension (systolic blood
pressure >160 mmHg or diastolic blood pressure >105 mmHg), a recent major operation
(<3 months), autoimmune disease, or metabolic syndrome. In addition, patients with previous
histories of anemia and those who had received previous red blood cell transfusions or were being
treated for anemia (e.g., with supplemental iron, folate, or an erythropoiesis-stimulating agent)
were not included in this study. Patients with known hematological disease, such as hemolytic
anemia, neoplastic metastases to the bone marrow, or iron replacement therapy, which could increase
plasma RDW levels, were also excluded.
The baseline characteristics of all enrolled subjects were recorded, including age, gender, body mass index (BMI), diabetes mellitus, hypertension, dyslipidemia, smoking, family history of coronary artery disease, left ventricular ejection fraction, creatinine level, and current medications.
Coronary angiography
Elective coronary angiography was performed for all enrolled patients using the standard Judkins technique, and the results were analyzed by at least two interventional physicians, as in our previous study (1717. Li J-J, Wang H-R, Huang C-X, Xue J-L, Li G-S. Enhanced response of blood monocytes to C-reactive protein in patients with unstable angina. Clin Chim Acta. 2004;22:352(1-2):127-33.). Only angiograms with visually smooth contours with no wall irregularities were considered to be normal. Iopromide was used as a contrast in the angiography (Ultravist-370, Schering AG, Berlin, Germany).
Assessment of coronary blood flow
The coronary flow rates of all subjects were determined by the thrombosis in myocardial
infarction (TIMI) frame counts (TFCs) because the method is a simple, reproducible, objective, and
quantitative index of coronary flow velocity (1818. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ. et al
TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation.
1996;93(5):879-88, http://dx.doi.org/10.1161/01.CIR.93.5.879.
http://dx.doi.org/10.1161/01.CIR.93.5.87...
). A TFC was
determined for each major coronary artery in each patient and control subject according to the
method first described by Gibson et al. (1818. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ. et al
TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation.
1996;93(5):879-88, http://dx.doi.org/10.1161/01.CIR.93.5.879.
http://dx.doi.org/10.1161/01.CIR.93.5.87...
). Briefly, the
number of cineangiographic frames (recorded at 30 frames per second) required for the leading edge
of the column of radiographic contrast to reach a predetermined landmark is determined. The first
frame is defined as the frame in which the concentrated dye occupies the full width of the proximal
coronary artery lumen, touching both borders of the lumen and exhibiting forward motion in the
artery. The final frame is designated when the leading edge of the contrast column initially arrives
at the distal landmark. In the left anterior descending (LAD) coronary artery, the landmark used is
the most distal branch nearest the apex of the left ventricle, commonly referred to as a
“pitchfork”. All antianginal and anti-ischemic medications, except for sublingual
nitroglycerin, were withheld for at least 24 hours before the examination. To exclude the
possibility of a coronary spasm during coronary angiography, all patients underwent hyperventilation
tests, which were performed by asking the patients to breathe quickly and deeply for at least five
minutes.
The mean TFC for each patient and control subject was calculated by adding the TFCs of the LAD
artery, left circumflex artery (LCX), and right coronary artery (RCA) and then dividing the sum by
three. All participants with a TFC >27 were diagnosed with SCFS (1818. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ. et al
TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation.
1996;93(5):879-88, http://dx.doi.org/10.1161/01.CIR.93.5.879.
http://dx.doi.org/10.1161/01.CIR.93.5.87...
). The mean TFCs reported by the two independent observers were compared to
assess inter-observer reliability. A discrepancy was subsequently resolved by a third observer. For
the first 30 coronary angiograms, the reviewing process was repeated at the end of the study to
determine intra-observer variability.
Determinations of RDW and C-reactive protein (CRP)
Erythrocyte count, hemoglobin, RDW, corpuscular volume, and white blood cell (WBC) count were determined using the automated hematology analyzer XE-1200 (Sysmex, Kobe, Japan). The normal range of RDW (%) in our laboratory was 10-16%. The other biochemical measurements were performed using a molecular analyzer (Roche Diagnostics, Manheim, Germany).
EDTA-anticoagulated peripheral blood samples were collected after a 12-hour overnight fast at baseline (before the coronary angiography). The plasma was obtained after centrifugation at 3000 rpm at 4°C for 15 minutes. The levels of high-sensitivity CRP were determined using immunoturbidimetry (Beckmann Assay 360), as in our previous study (1717. Li J-J, Wang H-R, Huang C-X, Xue J-L, Li G-S. Enhanced response of blood monocytes to C-reactive protein in patients with unstable angina. Clin Chim Acta. 2004;22:352(1-2):127-33.). The median normal CRP value was 0.08 mg/dL, with 90% of normal values <0.03 mg/dL and with a lower detection limit of 0.02 mg/dL. The inter-assay and intra-assay coefficients of variation were 4.5% and 5.0%, respectively. Finally, to assess the potential relationship between RDW levels and TFCs or CRP, a correlation analysis was performed for patients with SCFS.
Statistical analysis
The continuous variables are expressed as the mean±standard deviation (SD), and the categorical variables are expressed as percentages. A comparison of continuous variables between the two groups was performed using Student's t-test and/or the Mann-Whitney U-test. The chi-squared test or Fisher's exact test was used to compare the categorical variables between the two groups. Because the CRP distribution is skewed rightward, a log transformation was performed at baseline, and the significance of any difference in the distributions was assessed with the Wilcoxon rank-sum test, as in our previous study (1717. Li J-J, Wang H-R, Huang C-X, Xue J-L, Li G-S. Enhanced response of blood monocytes to C-reactive protein in patients with unstable angina. Clin Chim Acta. 2004;22:352(1-2):127-33.). Univariate and multivariate analyses were used for the baseline clinical characteristics, inflammatory biomarkers, and RDW. The association between RDW and CRP or TFC was tested using Spearman's correlation coefficient. The SCFS patients were divided into three groups using the upper tertile of the baseline RDW and CRP values as a prespecified cutoff (RDW, 13.8% and CRP, 3 mg/dL). A p-value <0.05 was considered statistically significant.
RESULTS
Baseline clinical characteristics
The baseline clinical characteristics of the SCFS patients (n = 185) or the age- and gender-matched normal controls (n = 183) are summarized in Table 1. There were no significant differences between the SCFS group and the controls in the following baseline clinical variables: age, BMI, family history of coronary artery disease, left ventricle function, the mean diameter of the coronary arteries, and medications. However, the risk factors for cardiovascular disease, such as current smoking, hypertension, dyslipidemia, and diabetes, were higher in the SCFS patients than in the normal controls, although a higher TFC was found in the SCFS patients (Table 1).
Laboratory findings
As shown in Table 2, there were no differences in laboratory variables, including erythrocyte count, mean corpuscular volume, hemoglobin, and creatinine, between the two groups. However, the WBC counts, monocyte counts, and plasma CRP levels were higher in the SCFS patients than in the controls (WBC count, 6836±1130/mm3 versus 6327±1092/mm3, p = 0.047; monocyte count, 641±162/mm3 versus 609±147/mm3, p = 0.035; CRP level, 0.29±0.16 mg/L versus 0.21±0.14 mg/L, p = 0.042). In addition, the pattern of the RDW levels was similar to the pattern of the CRP levels, with elevated RDW levels in the SCFS patients compared to the controls (13.5±1.8 versus 12.8±1.6, p = 0.031).
Univariate and multivariate analyses
In this study, the seven variables associated with SCFS, including smoking, hypertension, dyslipidemia, diabetes, peripheral circulating WBCs, monocytes, CRP and RDW (p<0.05 in the univariate analysis) are presented in Table 3 (smoking, odds ratio [OR] 1.354, 95% confidence interval [CI], 1.081-1.593, p = 0.031; diabetes, OR 1.286, 95% CI, 1.052-1.476, p = 0.046; hypertension, OR 1.277, 95% CI, 1.048-1.432, p = 0.050; WBCs, OR 1.287, 95% CI, 1.071-1.840, p = 0.051; monocytes, OR 1.426, 95% CI, 1.157-1.885, p = 0.041; CRP, OR 1.901, 95% CI, 1.292-3.127, p = 0.015; RDW, OR 1.962, 95% CI, 1.319-3.348, p = 0.003). We then included these seven variables in a multivariate analysis. Interestingly, we found that RDW (tertile, >13.8%) and CRP (tertile, >3 mg/dL) were the independent variables most strongly associated with SCFS (RDW, OR 3.973, 95% CI, 1.352-4.262, p = 0.001; CRP, OR 3.112, 95% CI, 1.226-3.633, p = 0.018; Table 4.
Correlation between RDW and CRP or TFC
A linear correlation analysis was first performed to determine the relationship between the RDW and CRP levels in the SCFS patients. In addition, the correlation between the RDW and mean TFCs was also analyzed. A significantly positive correlation between the RDW levels and CRP (Figure 1), n = 185, γ = 0.382, p = 0.014) or mean TFCs (Figure 2), n = 185, γ = 0.531, p = 0.001) was detected.
Correlation of RDW levels and plasma CRP concentrations in patients with SCF. There was a positive correlation between the RDW levels and CRP concentrations (n = 185, γ = 0.382, p = 0.014).
Correlation of RDW levels and in TFCs in patients with SCF. There was a positive correlation between the RDW levels and TFC (n = 185, γ = 0.531, p = 0.001).
DISCUSSION
In the present study, we demonstrated for the first time that higher RDW levels exist in SCFS patients. In addition, the data showed that baseline RDW levels are an independent predictor of this unique disorder. Finally, our study indicated that there is a strongly positive correlation between the RDW levels and CRP or TFCs in patients with SCFS. Taken together, the results of the present study indicate that RDW may be a useful marker for detecting the presence of SCFS.
SCFS was first described as early as 1972. A limited number of studies have focused on the
etiology of this uncommon angiographic phenomenon since that time, and the pathophysiological
mechanism of SCFS remains largely unclear; however, several potential hypotheses have been
suggested, such as the organic or functional dysfunction of small coronary arteries, an earlier form
of atherosclerosis, platelet aggregability, and an imbalance between vasoconstricting and
vasodilating factors (33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
). Inflammation has been considered to
be a major contributing factor in many cardiovascular events and is associated with different
clinical settings of coronary artery disease, which may be involved in SCFS development. In fact,
Turhan et al. found that serum intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion
molecule-1 (VCAM-1), and E-selectin levels were higher in SCFS patients than in NCF patients.
Moreover, these increased soluble ICAM-1, VCAM-1, and E-selectin levels were significantly
correlated with average TFCs in SCFS patients (1919. Turhan H, Saydam GS, Erbay AR, Ayaz S, Yasar AS, Aksoy Y, et al. Increased
plasma soluble adhesion molecules: ICAM-1, VCAM-1, and E-selectin levels in patients with slow
coronary flow. Int J Cardiol. 2006;108(2):224-30.). Our
previous study also demonstrated that increased plasma IL-6 levels were related to the presence of
SCFS (2020. Li J-J, Qin X-W, Li Z-C, Zeng H-S, Gao Z, Xu B, et al. Increased plasma
C-reactive protein and interleukin-6 levels in patients with slow coronary flow. Clin Chim Acta.
2007;385(1-2):43-7, http://dx.doi.org/10.1016/j.cca.2007.05.024.
http://dx.doi.org/10.1016/j.cca.2007.05....
). Therefore, we hypothesized that SCFS might be a
syndrome that is strongly associated with an inflammatory response (33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
,2020. Li J-J, Qin X-W, Li Z-C, Zeng H-S, Gao Z, Xu B, et al. Increased plasma
C-reactive protein and interleukin-6 levels in patients with slow coronary flow. Clin Chim Acta.
2007;385(1-2):43-7, http://dx.doi.org/10.1016/j.cca.2007.05.024.
http://dx.doi.org/10.1016/j.cca.2007.05....
).
An increased RDW results from heterogeneity in the size of erythrocytes and erythrocyte
fragmentation in the circulation. The RDW is generally used in combination with the mean corpuscle
volume as an indicator in the differential diagnosis of anemia (2121. Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohaszka Z, Janoskuti L. Red cell
distribution width in heart failure: prediction of clinical events and relationship with markers of
ineffective erythropoiesis, inflammation, renal function, and nutrition state. Am Heart J.
2009;158(4):659-66, http://dx.doi.org/10.1016/j.ahj.2009.07.024.
http://dx.doi.org/10.1016/j.ahj.2009.07....
). Factors that contribute to the increased heterogeneity of erythrocyte size include iron
or vitamin B12/folate deficiency, decreased erythrocyte lifespan, impaired erythropoiesis, and
factors that contribute to erythrocyte fragmentation, including increased fragility and the
destruction of red blood cells (2222. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of
chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow
erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood.
2002;100(2):474-82, http://dx.doi.org/10.1182/blood-2002-01-0136.
http://dx.doi.org/10.1182/blood-2002-01-...
,2323. Cakal B, Akoz AG, Ustundag Y, Yalinkilic M, Ulker A, Ankarali H. Red cell
distribution width for assessment of activity of inflammatory bowel disease. Dig Dis Sci.
2009;54(4):842-7, http://dx.doi.org/10.1007/s10620-008-0436-2.
http://dx.doi.org/10.1007/s10620-008-043...
). Recently, an elevated RDW was found to be a strong and independent predicator
of an increased risk of mortality and adverse cardiovascular outcomes in patients with acute and
chronic cardiac conditions (44. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, et al. Red cell
distribution width as a novel prognostic marker in heart failure: data from the CHARM program and
the Duke database. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
5. Lappe JM, Home BD, Shah SH, May HT, Muhlestein JB, Lappe DL, et al. Red cell
distribution widtd, C-reactive protein, the complete blood count, and mortality in patients with
coronary disease and a normal comparison polpulation. Clin Chim Acta. 2011;412(23-24):2094-9,
http://dx.doi.org/10.1016/j.cca.2011.07.018.
http://dx.doi.org/10.1016/j.cca.2011.07....
6. Dabbah S, Hammerman H, Markiewicz W, Aronson D. Relation between red cell
distribution width and clinical outcomes after acute myocardial infarction. Am J Cardiol.
2010;105(3):312-7, http://dx.doi.org/10.1016/j.amjcard.2009.09.027.
http://dx.doi.org/10.1016/j.amjcard.2009...
7. Tonelli M, Sacks F, Arnold M, Moye L, Davis B, Pfeffer M. Cholesterol and
Recurrent Events Trial Investigators. Relation between red blood cell distribution width and
cardiovascular event rate in peoples with coronary disease. Circulation. 2008;117(2):163-8,
http://dx.doi.org/10.1161/CIRCULATIONAHA.107.727545.
http://dx.doi.org/10.1161/CIRCULATIONAHA...
8. Ye Z, Smith C, Kullo IJ. Usefulness of red cell distribution width to predict
mortality in patients with peripheral artery disease. Am J Cardiol. 2011;107(8):1241-5,
http://dx.doi.org/10.1016/j.amjcard.2010.12.023.
http://dx.doi.org/10.1016/j.amjcard.2010...
9. Dogdu O, Koc F, Kalay N, Yarliglues M, Elicik D, karayakali M, Ozbek K, Kaya MG.
Assessment of red cell distribution width (RDW) in patients with coronary artery ectasia. Clin Appl
Thromb Hemost. 2012;18(2):211-214, http://dx.doi.org/10.1177/1076029611418964.
http://dx.doi.org/10.1177/10760296114189...
10. Ani C, Ovbiagele B. Elevated red blood cell distribution width to predicts
mortality in persons with known stroke. J Neurol Sci. 2009;277(1-2):103-8,
http://dx.doi.org/10.1016/j.jns.2008.10.024.
http://dx.doi.org/10.1016/j.jns.2008.10....
11. Karabulut A, Uyarel H, Uzunlar B, Cakmak M. Elevated red cell distribution level
predicts worse postinterventional thrombosis in myocardial infarction flow reflecting abnormal
reperfusion in acute myocardial infarction treated with a primary coronary intervention. Coron
Artery Dis. 2012;23(1):68-72, http://dx.doi.org/10.1097/MCA.0b013e32834f1188.
http://dx.doi.org/10.1097/MCA.0b013e3283...
12. Lsik T, Kurt M, Ayhan E, Tanboga IH, Ergelen M, Uyarel H. The impact of
admission red cell distribution width on the development of poor myocardial perfusion after primary
percutaneous intervention. Atherosclerosis. 2012;224(1):143-9.
13. Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJV, Pfeffer MA, et al. Red
cell distribution width as a novel prognostic marker in heart failure - Data from the CHARM program
and the Duke Databank. J Am Coll Cardiol. 2007;50(1):40-7,
http://dx.doi.org/10.1016/j.jacc.2007.02.067.
http://dx.doi.org/10.1016/j.jacc.2007.02...
14. Allen LA, Felker GM, Mehra MR, Chiong JR, Dunlap SH, Ghali JK, et al. Validation
and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.
J Cardial Fail. 2010;16(3):230-8,
http://dx.doi.org/10.1016/j.cardfail.2009.11.003.
http://dx.doi.org/10.1016/j.cardfail.200...
15. Patel KV, Semba RD, Ferrucci L, Newman AB, Fried LP, Wallace RB, et al. Red cell
distribution width and mortality in older adults: a meta-analysis. J Gerontol A Biol
Sci Med Sci. 2010;65(3):258-65, http://dx.doi.org/10.1093/gerona/glp163.
http://dx.doi.org/10.1093/gerona/glp163...
-1616. Peristein TS, Weuve J, Pfeffer MA, Beckman JA. Red blood cell distribution width
and mortality risk in a community-based prospective cohort. Arch Intern Med. 2009;169(6):588-94,
http://dx.doi.org/10.1001/archinternmed.2009.55.
http://dx.doi.org/10.1001/archinternmed....
). Although these studies demonstrated the role of RDW in a variety of cardiovascular
diseases, the association between RDW levels and SCFS has not yet been assessed. In the present
study, we elaborated on the results of previous studies and found, for the first time, that RDW is
significantly higher in SCFS patients than in normal controls (13.5±1.8 versus
12.8±1.6, p = 0.031). A multivariate analysis showed that the
upper tertile of RDW (>13.8%) was an independent predictor of SCFS (OR 3.973, 95% CI
1.352-4.262, p = 0.018). Our data may provide information regarding
the role of RDW in cardiovascular diseases.
The exact mechanism underlying the correlation between higher levels of RDW and the presence of
SCFS is relatively unknown. One of the most likely mechanisms is inflammation. In fact, recent
findings have suggested that inflammation may play a pathogenic role in SCFS (33. Li J-J, Xu B, Li Z-C, Qian J, Wei BQ. Is slow coronary flow associated with
inflammation. Med Hypotheses. 2006;66(3):504-8,
http://dx.doi.org/10.1016/j.mehy.2005.09.028.
http://dx.doi.org/10.1016/j.mehy.2005.09...
). A higher RDW was associated with inflammatory markers, such as soluble tumor
necrosis factor receptors and CRP, in atherosclerosis and other chronic diseases (2121. Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohaszka Z, Janoskuti L. Red cell
distribution width in heart failure: prediction of clinical events and relationship with markers of
ineffective erythropoiesis, inflammation, renal function, and nutrition state. Am Heart J.
2009;158(4):659-66, http://dx.doi.org/10.1016/j.ahj.2009.07.024.
http://dx.doi.org/10.1016/j.ahj.2009.07....
,2222. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of
chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow
erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood.
2002;100(2):474-82, http://dx.doi.org/10.1182/blood-2002-01-0136.
http://dx.doi.org/10.1182/blood-2002-01-...
). A strong association
between RDW and inflammatory markers was found in a large cohort of unselected adult outpatients and
in patients with inflammatory bowel disease (2323. Cakal B, Akoz AG, Ustundag Y, Yalinkilic M, Ulker A, Ankarali H. Red cell
distribution width for assessment of activity of inflammatory bowel disease. Dig Dis Sci.
2009;54(4):842-7, http://dx.doi.org/10.1007/s10620-008-0436-2.
http://dx.doi.org/10.1007/s10620-008-043...
).
Proinflammatory cytokines may also contribute to the heterogeneity of the erythrocyte population
through other pathways, such as oxidative stress (2424. Wang T, Zhang X, Li J-J. The role of NF-kappaB in the regulation of cell stress
responses. Int Immunopharmacol. 2002;2(11):1509-20,
http://dx.doi.org/10.1016/S1567-5769(02)00058-9.
http://dx.doi.org/10.1016/S1567-5769(02)...
). Red
blood cells have a large antioxidant capacity and serve as a primary oxidative sink, but these cells
are prone to oxidative damage, which reduces cell survival and induces the release of juvenile
erythrocytes into the circulation (2525. Gul M, Uyarel H, Ergelen M, Karacimen D, Uger M, Turer A, et al. The
relationship between red blood cell distribution width and the clinical outcomes in non-ST elevation
myocardial infarction and unstable angina pectoris: a 3-year follow-up. Coron Artery Dis.
2012;23(5):330-6., http://dx.doi.org/10.1097/MCA.0b013e3283564986
http://dx.doi.org/10.1097/MCA.0b013e3283...
). In the present study,
the data first demonstrated that elevated plasma CRP was higher in the SCFS patients compared with
the normal controls (0.29±0.16 mg/L versus 0.21±0.14 mg/L,
p = 0.042). A positive correlation between RDW and plasma CRP or TFCs was then found
in the SCFS patients, thereby suggesting that an inflammatory mechanism may be involved in higher
RDW levels in SCFS patients.
In conclusion, in this prospective, age- and gender-matched case-control study, the data demonstrated, for the first time, that RDW levels are higher and positively correlated with CRP and TFC in SCFS patients. This finding suggests that RDW may be a useful marker and predictor for SCFS.
LIMITATIONS
The small sample size may be a study limitation. Other factors, including iron, vitamin B12, and folate, were not measured in this study.
This research was partially supported by the National Natural Scientific Foundation (81070171), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20111106110013), and the Fund of Capital Special Foundation of Clinical Application Research (Z121107001012015), which was awarded to Jian-Jun Li, MD, PhD.
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» http://dx.doi.org/10.1016/j.cardfail.2009.11.003 -
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» http://dx.doi.org/10.1093/gerona/glp163 -
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» http://dx.doi.org/10.1001/archinternmed.2009.55 -
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20Li J-J, Qin X-W, Li Z-C, Zeng H-S, Gao Z, Xu B, et al. Increased plasma C-reactive protein and interleukin-6 levels in patients with slow coronary flow. Clin Chim Acta. 2007;385(1-2):43-7, http://dx.doi.org/10.1016/j.cca.2007.05.024.
» http://dx.doi.org/10.1016/j.cca.2007.05.024 -
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» http://dx.doi.org/10.1016/j.ahj.2009.07.024 -
22Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood. 2002;100(2):474-82, http://dx.doi.org/10.1182/blood-2002-01-0136.
» http://dx.doi.org/10.1182/blood-2002-01-0136 -
23Cakal B, Akoz AG, Ustundag Y, Yalinkilic M, Ulker A, Ankarali H. Red cell distribution width for assessment of activity of inflammatory bowel disease. Dig Dis Sci. 2009;54(4):842-7, http://dx.doi.org/10.1007/s10620-008-0436-2.
» http://dx.doi.org/10.1007/s10620-008-0436-2 -
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» http://dx.doi.org/10.1016/S1567-5769(02)00058-9 -
25Gul M, Uyarel H, Ergelen M, Karacimen D, Uger M, Turer A, et al. The relationship between red blood cell distribution width and the clinical outcomes in non-ST elevation myocardial infarction and unstable angina pectoris: a 3-year follow-up. Coron Artery Dis. 2012;23(5):330-6., http://dx.doi.org/10.1097/MCA.0b013e3283564986
» http://dx.doi.org/10.1097/MCA.0b013e3283564986
Publication Dates
-
Publication in this collection
June 2013
History
-
Received
7 Nov 2012 -
Reviewed
22 Nov 2012 -
Accepted
14 Dec 2012