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Chronic Kidney Disease and Coronary Artery Vulnerable Plaques Mitsuru Wada,* Yasunori Ueda,* Tomoaki Higo,† Koshi Matsuo,* Mayu Nishio,* Akio Hirata,* Mitsutoshi Asai,* Takayoshi Nemoto,* Toshikazu Kashiyama,* Ayaka Murakami,* Kazunori Kashiwase,* and Kazuhisa Kodama*

Summary Background and objectives Chronic kidney disease (CKD) is a risk factor of cardiovascular disease. The number of yellow plaques is a predictor of future cardiovascular events. We assumed that CKD might raise the risk of cardiovascular events by increasing the number of yellow plaques. Therefore, we compared the number of yellow plaques between patients with and without CKD. Design, setting, participants, & measurements Consecutive 136 patients with acute myocardial infarction who received percutaneous coronary intervention (PCI) and angioscopic examination were analyzed. The infarct-related artery was angioscopically examined. The number of yellow plaques, maximum yellow color grade of detected yellow plaques, and prevalence of disrupted yellow plaques in nonculprit segments were compared between patients with and without CKD. Results The number of yellow plaques was significantly larger in CKD than in non-CKD patients (median [interquartile range]: 4.0 [2.0 to 6.0] versus 2.0 [1.0 to 4.0], P ⫽ 0.001). Maximum yellow color grade and prevalence of disrupted plaques in the nonculprit segments were not different between patients with and without CKD. Multivariate logistic regression analysis revealed CKD as an independent risk of multiple yellow plaques per vessel (odds ratio 3.49, 95% confidence interval 1.10 to 11.10, P ⫽ 0.03).

*Cardiovascular Division, Osaka Police Hospital, Osaka, Japan; and †Osaka University Graduate School of Medicine, Suita, Japan Correspondence: Dr. Yasunori Ueda, Cardiovascular Division, Osaka Police Hospital, 10-31 Kitayama-cho, Tennojiku, Osaka, 543-0035 Japan. Phone: ⫹81-66771-6051; Fax: ⫹816-6775-2845; E-mail: [email protected]

Conclusion CKD was an independent risk factor of multiple coronary yellow plaques, suggesting that patients with CKD would have a higher risk of coronary events because they had more yellow plaques than patients without CKD. Clin J Am Soc Nephrol 6: 2792–2798, 2011. doi: 10.2215/CJN.06780711

Introduction Chronic kidney disease (CKD) has recently been recognized as an independent risk factor of cardiovascular disease (1–5). However, the mechanisms how CKD increases the risk have not been fully understood: it may accelerate the formation of vulnerable plaques; it may increase the frequency of plaque disruption; and/or it may increase the thrombogenicity of blood. On the other hand, we have revealed in a previous angioscopic study (6) that the number of yellow plaques in a coronary artery is an independent risk of cardiovascular events and that patients with multiple yellow plaques per vessel have 2.2-fold higher risk of suffering acute coronary syndrome (ACS) than patients with no or a single yellow plaque per vessel. Therefore, we assumed that CKD would raise the risk of cardiovascular events by increasing the number of yellow plaques. Yellow plaques, especially the yellow plaques of higher yellow color intensity, are regarded as vulnerable plaques that are supposed major cause of ACS and stenosis progression by their disruption followed by thrombus 2792

Copyright © 2011 by the American Society of Nephrology

formation. In the present study, we compared the number of yellow plaques between patients with and without CKD to clarify the influence of CKD on the number of yellow plaques.

Materials and Methods Study Patients A total of 136 consecutive patients with acute myocardial infarction (MI) with/without ST elevation who received PCI and angioscopic examination from February 2002 to April 2008 were analyzed. Acute MI was diagnosed by the elevation of serum troponin: T ⱖ 0.1 ng/ml, the symptom onset being within a 12-hour duration, and the changes on electrocardiography (ST-segment elevation/depression of 1 mm in two contiguous leads or new left bundle branch block). Although it is recommended to perform an angioscopic examination, it was performed only when (1) the target vessel was suitable for angioscopic examination, (2) the angioscopy device and specialist were available at the time of catheterization, and (3) adequate time was available for angioscopic examination. www.cjasn.org Vol 6 December, 2011

Clin J Am Soc Nephrol 6: 2792–2798, December, 2011

Patients were divided into the CKD or the non-CKD group according to the estimated GFR evaluated on admission. The estimated GFR was calculated using the Modification of Diet in Renal Disease equation and was based on indirect calibration of serum creatinine (7). CKD was defined as estimated GFR ⬍60 ml/min per 1.73 m2. The infarct related artery was angioscopically examined after PCI, and the number of yellow plaques, the maximum yellow color grade, and the prevalence of disrupted yellow plaques in the nonculprit segments were determined for each patient and were compared between CKD and non-CKD groups. Non-infarct-related arteries were not examined. Multivariate logistic regression analysis was also performed to clarify the associated factors for the multiple coronary yellow plaques that had been proven to be an independent risk of future ACS events (6). Intravenous heparin (100 U/kg) was administered at the beginning of catheterization, and an additional dose was repeated at the time of PCI as a routine protocol in our hospital. Glycoprotein-IIb/IIIa blockers were not used in any patient because they were not approved in Japan. Study patients were followed up for cardiovascular events during hospitalization and at the outpatient clinic. Cardiovascular events included death of any cause and occurrence of ACS. ACS was defined as acute MI or unstable angina. Occurrence of ACS was comprehensively diagnosed by symptom, electrocardiogram, blood tests, echocardiogram, myocardial scintigram, coronary computed tomography, and/or coronary angiogram. When ACS was suspected, we strongly recommended coronary angiography. Hypertensive patients were defined as those with BP ⬎140/90 mmHg or those already taking antihypertensive drugs. Patients with diabetes were defined as those with fasting blood glucose ⱖ126 mg/dl or those already taking oral drugs for diabetes mellitus or receiving insulin therapy. Obesity was defined as body mass index (BMI ⫽ weight [kg]/height [m2]) ⬎ 26.4. Written informed consent was acquired from all patients. This protocol was approved by the Osaka Police Hospital Ethical Committee. Angioscopic Procedures and Evaluations Catheterization was performed by femoral, brachial, or radial artery approach using a 6- or 7-Fr sheath and catheters. The coronary angiogram was recorded using the Advantx medical system (GE Healthcare Japan, Tokyo, Japan). The angioscope RX-3310A and MV-5010A (Machida, Tokyo, Japan) and optic fiber DAG-2218LN (Machida) were used. The angioscopic observation was made while blood was cleared away from view by the injection of 3% dextran-40 as we previously reported (8). Yellow plaque was defined simply as the yellow area on the luminal surface, which might have a smooth or irregular surface with or without protrusion into the lumen (6). Yellow color grade of all detected yellow plaques in the nonculprit segments was classified into three grades (1, slight yellow; 2, yellow; 3, intense yellow) according to the standard colors (Figure 1A) as we previously reported (9), and the maximum yellow color grade of the yellow plaques and the number of yellow plaques in the vessel were determined for each patient

CKD and Coronary Yellow Plaques, Wada et al.

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Figure 1. | A representative case and standard colors for grade classification. (A) Standard colors for grading yellow plaques. The grade of yellow color was compared with these standard colors: grade 0, white; grade 1, slight yellow; grade 2, yellow; and grade 3, intense yellow. (Source: Ueda et al. [9]). (B) Angioscopic examination was performed after percutaneous coronary intervention in the left anterior descending coronary artery. The number of yellow plaques was eight, and the maximum yellow color grade was 3. There were four disrupted yellow plaques (red numbers: 3, 4, 7, and 8): the culprit lesion is marked 3, and the other in the nonculprit segments.

as we previously reported (6). The atherosclerosis index was defined as (number of yellow plaques) ⫻ (maximum yellow color grade) as previously reported (9). Thrombus was defined as white or red material that had a cotton-like or ragged appearance or that presented fragmentation with or without protrusion into the lumen or adherent to the luminal surface. Disrupted yellow plaque was defined as the yellow plaque that had thrombus on it. Presence or absence of disrupted yellow plaque in the nonculprit segments of the artery was determined for each patient. All major coronary arteries were divided equally into three segments, i.e., proximal, mid, and distal segments, and the spatial distribution of yellow plaques was analyzed. Angioscopic evaluations were made by two specialists of angioscopy who were blinded to patients’ characteristics, and in case of disagreement a third reviewer served as an arbitrator. The interobserver and intraobserver reproducibility for the interpretation of angioscopic images was 85% and 95% for plaque color and 90% and 100% for thrombus, respectively. A representative case is presented in Figure 1B.

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Statistical Analyses Continuous variables with normal distribution were expressed as mean ⫾ SD, and those with non-normal distribution were expressed as median and interquartile range (IQR). Normal distribution of continuous variables was checked by visual assessment of Q-Q plots and Kolmogorov-Smirnov test. The independency of parameters was judged with a correlation matrix from the statistical and medical viewpoints. Comparisons were made between groups by unpaired t test, chi-squared test, or Mann-Whitney/KruskalWallis test. Because angioscopic parameters were not normally distributed, they were compared by nonparametric analyses and were log-transformed for linear regression analysis. To determine the significant factors associated with multiple yellow plaques or the number of yellow plaques, multivariate logistic regression analysis and linear regression analysis were performed including CKD, age, gender, hypertension, hypercholesterolemia, diabetes mellitus, and current smoking as independent variables. Cumulative event rates were estimated by the Kaplan-Meier method and tested by log-rank statistics. P ⬍ 0.05 was regarded as statistically significant. Analysis was done with SPSS version 16.0J for Windows (SPSS Inc., Chicago, Illinois).

Results Association between CKD and the Number of Yellow Plaques Among study patients, 43 patients were classified as CKD and 93 patients as non-CKD. However, only two patients had severe CKD with estimated GFR ⬍30ml/min per 1.73 m2. Patients’ characteristics are presented in Table 1, and no CKD patients were receiving hemodialysis. Among all 136 patients, 444 yellow plaques (median 3.0 [IQR 2.0 to 5.0] yellow plaques/patient) were detected by angioscopic examinations. The distribution of the number of yellow plaques is presented in Figure 2, which appears shifted to the larger number in CKD patients compared with non-CKD patients. Spatial distribution of yellow plaques was not different between CKD and non-CKD patients (proximal/mid/distal: 57%/39%/4% versus 61%/ 34%/5%, P ⫽ 0.60). The distribution of the yellow color grade at culprit lesions (grade 0/grade 1/grade 2/grade 3: 0%/3%/62%/35% versus 5%/6%/48%/42%, P ⫽ 0.36) was not different between CKD and non-CKD patients. The number of yellow plaques and the atherosclerosis index (Table 2) were significantly larger in CKD than in

Table 1. Patients’ characteristics

2

eGFR (ml/min per 1.73 m ) Age (years) Male gender Hypertension Serum lipid levels (mg/dl) total cholesterol LDL cholesterol HDL cholesterol triglyceride Diabetes mellitus Current smoking Obesity Multivessel disease Condition of CKD diagnosed on entry on medication on hemodialysis Diagnosis STEMI NSTEMI Culprit vessel LAD LCX RCA Medicationsa aspirin ticlopidin/clopidogrel statin ACEI/ARB ß-blocker Ca blocker

CKD (n ⫽ 43)

Non-CKD (n ⫽ 93)

P

48.0 ⫾ 9.7 69 ⫾ 12 30 (70) 34 (79)

78.1 ⫾ 13.9 62 ⫾ 10 80 (86) 79 (85)

⬍0.001 0.02 0.001 0.39

204 ⫾ 38 127 ⫾ 32 46 ⫾ 11 158 ⫾ 120 9 (21) 19 (44) 5 (12) 14 (33)

212 ⫾ 36 135 ⫾ 32 46 ⫾ 10 155 ⫾ 91 33 (36) 46 (50) 21 (23) 34 (37)

0.23 0.17 0.69 0.87 0.08 0.56 0.13 0.65

34 (79) 2 (5) 0 (0)

— — —

40 (93) 3 (7)

84 (90) 9 (10)

12 (28) 7 (16) 24 (56)

55 (59) 8 (9) 30 (32)

6 (14) 2 (5) 4 (9) 2 (5) 3 (7) 3 (7)

9 (10) 2 (2) 8 (9) 8 (9) 3 (3) 14 (15)

0.75 0.004

0.55 0.59 1.00 0.50 0.38 0.26

Values are mean ⫾ SD or the number of subjects with percentage in parentheses. CKD, chronic kidney disease; —, not applicable; eGFR, estimated GFR; LDL, low-density lipoprotein; HDL, high-density lipoprotein; STEMI, ST elevation myocardial infarction; NSTEMI, non-ST elevation myocardial infarction; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker. a Medications that patients were taking before arriving at our hospital.


Figure 2. | Distribution of the number of yellow plaques comparing in chronic kidney disease (CKD) compared with non-CKD patients. The number of yellow plaques was larger number in CKD patients than in non-CKD patients.

non-CKD patients, in the patients with hypercholesterolemia than in those without, and in the patients with more risk factors. They were larger in the patients with lower estimated GFR when patients were divided into three groups: estimated GFR ⱖ60 ml per 1.73 m2 (n ⫽ 93), between 45 and 60 ml/min per 1.73 m2 (n ⫽ 32), and ⬍45 ml/min per 1.73 m2 (n ⫽ 11). Multivariate logistic regression analysis (Table 3) revealed CKD as an independent risk factor of multiple yellow plaques per vessel. Multivariate linear regression analysis (Table 4) revealed CKD, hypercholesterolemia, and hypertension as significant contributors for the number of yellow plaques per vessel. No statistically significant difference (P ⫽ 0.41 by logrank test) was detected in outcome between CKD and non-CKD patients: one death and no case of ACS was detected in CKD patients and no death or ACS was detected in non-CKD patients during hospitalization; four deaths and three cases of ACS were detected in CKD patients, and seven deaths and five cases of ACS were detected in non-CKD patients during 51 ⫾ 32 months of follow-up.

Association between CKD and the Maximum Yellow Color Grade Distribution of the maximum yellow color grade was not different between CKD and non-CKD patients (grade 1/grade 2/grade 3: 2%/42%/56% versus 7%/54%/40%, P ⫽ 0.17) or between patients with and without hypertension (5%/51%/44% versus 4%/48%/48%, P ⫽ 0.94), diabetes mellitus (5%/40%/55% versus 5%/54%/41%, P ⫽ 0.29), hypercholesterolemia (3%/51%/46% versus 8%/49%/43%, P ⫽ 0.43), current smoking (3%/49%/48% versus 7%/51%/ 42%, P ⫽ 0.52), or obesity (4%/50%/46% versus 6%/50%/ 44%, P ⫽ 0.94). Furthermore, the number of risk factors among hypertension, diabetes mellitus, hypercholesterolemia, and current smoking was not associated with the maximum yellow color grade (number of risk factors 0/1 versus 2 versus 3/4: 6%/53%/41% versus 9%/47%/44% versus 0%/51%/49%, respectively, P ⫽ 0.35).


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Association between CKD and the Prevalence of Disrupted Yellow Plaques in Nonculprit Segments The prevalence of disrupted yellow plaques in nonculprit segments was not different between CKD and nonCKD patients (40% versus 27%, P ⫽ 0.13) or between patients with and without hypertension (31% versus 30%, P ⫽ 0.95), diabetes mellitus (36% versus 29%, P ⫽ 0.41), hypercholesterolemia (34% versus 28%, P ⫽ 0.44), current smoking (29% versus 32%, P ⫽ 0.69), or obesity (31% versus 31%, P ⫽ 0.98). Furthermore, the number of risk factors among hypertension, diabetes mellitus, hypercholesterolemia, and current smoking was not associated with the presence of disrupted yellow plaques in nonculprit segments (number of risk factors 0/1 versus 2 versus 3/4: 28% versus 28% versus 36%, respectively, P ⫽ 0.62).

Discussion Although the mechanisms of how CKD increases the cardiovascular events have not been fully understood, we have revealed in the present study that patients with CKD have more coronary yellow plaques than those without CKD and that CKD is an independent risk of multiple yellow plaques per vessel, which we have previously demonstrated to be an independent risk factor for a future ACS event in a prospective clinical trial (6). Furthermore, more than half of yellow plaques in the CKD group represented grade 3, which is compatible with thin-cap fibroatheroma. Therefore, one of the mechanisms by which CKD is associated with a high risk of cardiovascular events would be through a large number of vulnerable coronary plaques. Findings on Yellow Plaques Summarized from Previous Reports Atherosclerotic lesions are detectable as yellow areas on the white vessel wall by angioscopy, i.e., yellow plaques. The intensity of the yellow color of the plaques has been inversely correlated with the thickness of fibrous cap and the superficial lipid depositions. Disrupted yellow plaques are detected in the majority of culprit lesions of ACS (9). Yellow plaques have been associated with adverse cardiovascular events and high thrombogenic potential. Furthermore, the yellow plaques of a higher grade of yellow color have been demonstrated to have a higher incidence of disruption (10) and to have a thinner fibrous cap (11). In our previous prospective study, the patients with more yellow plaques per vessel were found to have a higher risk of a future ACS event (6). Although grade 3 yellow plaques are compatible with thin-cap fibroatheroma defined by pathology (11), lower grade yellow plaques have also been shown to cause an ACS event (6). Furthermore, both ruptured plaques and nonruptured (eroded) plaques at the culprit lesions of ACS were yellow and had similar atherosclerotic characteristics (12). Therefore, the yellow plaques, especially those of a higher grade of yellow, are regarded as vulnerable plaques, including both of rupture-prone and erosion-prone vulnerable plaques. CKD and the Risk of Cardiovascular Events ACS is caused by the disruption of vulnerable plaques and the subsequent thrombus formation that disturbs coronary blood flow. Therefore, the risk of ACS would be determined by the number of vulnerable plaques, the vul-

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Table 2. Comparisons of the number of yellow plaques and atherosclerosis index

Number of Yellow Plaques

P

4.0 (2.0 to 6.0) versus 2.0 (1.0 to 4.0) 3.0 (2.0 to 5.0) versus 3.0 (1.0 to 5.0) 3.0 (2.0 to 5.0) versus 2.0 (1.0 to 4.0) 3.0 (2.0 to 5.0) versus 2.0 (1.8 to 4.0) 3.0 (2.0 to 5.0) versus 3.0 (2.0 to 4.0) 2.0 (1.8 to 4.3) versus 3.0 (2.0 to 5.0) 2.0 (1.0 to 4.0) versus 2.0 (2.0 to 4.0) versus 4.0 (2.0 to 5.0)

0.001 0.54 0.007 0.09 0.23 0.37 0.04

2.0 (1.0 to 4.0) versus 4.0 (2.3 to 6.0) versus 4.0 (2.0 to 6.0)

0.005

Atherosclerosis Index

P

9.0 (6.0 to 16.0) versus 6.0 (2.0 to 9.0) 6.0 (3.5 to 10.0) versus 8.0 (3.0 to 15.0) 8.0 (4.0 to 15.0) versus 6.0 (2.0 to 9.0) 9.0 (4.0 to 15.0) versus 6.0 (3.0 to 10.0) 8.0 (3.5 to 15.0) versus 6.0 (3.0 to 9.0) 6.0 (3.0 to 9.3) versus 6.0 (3.8 to 12.0) 6.0 (3.0 to 9.0) versus 6.0 (2.5 to 10.0) versus 9.0 (4.0 to 15.0)

0.001 0.55 0.01 0.05 0.19 0.46 0.04

6.0 (2.0 to 9.0) versus 9.0 (6.0 to 17.5) versus 12.0 (6.0 to 15.0)

0.004

CKD (yes versus no) Hypertension (yes versus no) Hypercholesterolemia (yes versus no) Diabetes mellitus (yes versus no) Current smoking (yes versus no) Obesity (yes versus no) Number of risk factors (0/1 versus 2 versus 3/4)a eGFR (ⱖ60 versus 45 to 60 versus ⬍45)

CKD (yes versus no) Hypertension (yes versus no) Hypercholesterolemia (yes versus no) Diabetes mellitus (yes versus no) Current smoking (yes versus no) Obesity (yes versus no) Number of risk factors (0/1 versus 2 versus 3/4)a eGFR (ⱖ60 versus 45 to 60 versus ⬍45)

CKD, chronic kidney disease; eGFR, estimated GFR (ml/min per 1.73 m2). Number of yellow plaques and atherosclerosis index are expressed as median and interquartile range. a Number of risk factors among hypertension, diabetes mellitus, hypercholesterolemia, and current smoking.

Table 3. Associated factors for the multiple coronary yellow plaques: multivariate analysis

Risk Factors

Odds Ratio

P

CKD Age Male gender Hypertension Hypercholesterolemia Diabetes mellitus Current smoking

3.49 (1.10 to 11.10) 0.99 (0.94 to 1.04) 0.24 (0.05 to 1.20) 1.11 (0.35 to 3.45) 2.27 (0.91 to 5.69) 1.96 (0.75 to 5.14) 1.26 (0.50 to 3.20)

0.03 0.64 0.08 0.86 0.08 0.17 0.62

CKD, chronic kidney disease. Multivariate logistic regression analysis was performed to determine the odds ratio among independent risk factors. Values in parentheses for the odds ratio are 95% confidence interval.

nerability of those plaques, the triggers of disruption, and the thrombogenic potential of the necrotic core and of blood. In the present study, CKD was demonstrated to have significant association with a large number of yellow plaques, i.e., vulnerable plaques. We have previously demonstrated in a prospective trial (6) that patients with ⱖ2 yellow plaques in a vessel have a higher incidence of an ACS event than those with no or a single yellow plaque. Therefore, CKD would be associated with high cardiovascular risk due to a large number of yellow plaques. Although CKD was not associated with a high frequency of higher-grade yellow plaques in the present study, both grade 2 and grade 3 yellow plaques, which generally have fibrous-cap thickness ⬍150 ␮m, have a probability of rupturing according to optical coherence tomography (OCT)

studies (11,13). CKD may also be associated with a high thrombogenic potential of blood, because the platelet reactivity under antiplatelet therapy has been reported to be higher in patients with CKD than in patients without CKD (14). Some factors such as endothelial dysfunction, oxidative stress, vascular calcification, inflammation, and anemia are supposed to be involved in the initiation and progression of coronary heart disease in patients with CKD (1–3). Hypercholesterolemia and other classic risk factors are known to contribute to both the formation of yellow plaques and the progression of CKD; therefore, the presence of multiple yellow plaques might be associated more strongly with CKD than with each classic risk factors. Although CKD is a risk marker that reflects combined risk of known classic coronary risk factors, it is also probable that CKD reflects combined risk of other unknown coronary risk factors or that CKD itself contributes to the progression of coronary disease through unknown mechanisms. However, patients with CKD would have a higher risk of coronary events, at least partly because they have more yellow plaques than patients without CKD. Subanalysis in our previous study (6) revealed that statin treatment was effective to reduce ACS events in the patients with multiple yellow plaques but not in the patients with fewer yellow plaques. Therefore, it is reasonable that statin treatment is more effective in CKD patients than in nonCKD patients (15) because it may reduce cardiac events by the regression and stabilization of vulnerable plaques (16). Study Limitations This was a cross-sectional study and could not demonstrate the causality between CKD and large number of



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Table 4. Associated factors for the number of coronary yellow plaques: multivariate analysis

Risk Factors

Odds Ratio

P

CKD Age Male gender Hypertension Hypercholesterolemia Diabetes mellitus Current smoking

166.59 (37.07 to 296.10) ⫺0.24 (⫺6.58 to 6.11) 44.13 (⫺109.03 to 197.29) ⫺159.98 (⫺313.83 to ⫺6.13) 181.91 (61.60 to 302.21) 19.30 (⫺76.35 to 174.94) 111.49 (⫺13.22 to 236.19)

0.01 0.94 0.56 0.04 0.003 0.43 0.07

CKD, chronic kidney disease. Multivariate linear regression analysis was performed to determine the contributors for the number of yellow plaques in a coronary artery among CKD, age, gender, hypertension, hypercholesterolemia, diabetes mellitus, and current smoking. The number of yellow plaques (NYP) was transformed into eNYP⫺1 to perform linear regression analysis. Values in parentheses for the odds ratio are 95% confidence interval.

yellow plaques. Because the patients with successful angioscopic examination were included in this study, those who had coronary arteries not suitable for angioscopic examination (e.g., diffusely stenotic or tortuous coronary arteries) were not included. We evaluated the number of yellow plaques but could not evaluate the size of yellow plaques, because the angioscopic device was unable to measure the distance or area on its image. However, the number of yellow plaques per vessel has been demonstrated to reflect the risk of future ACS event. Although the maximum yellow color grade and the prevalence of disrupted yellow plaques were not significantly different between CKD and non-CKD patients, this difference might become statistically significant if a larger number of patients were included. Because we evaluated estimated GFR on admission for acute MI, it might have been lower than that evaluated under usual conditions due to acute kidney injury. Most CKD patients in the present study had estimated GFR ⱖ30 ml/min per 1.73 m2; thus, we could not discuss the severe CKD patients who had estimated GFR ⬍30 ml/min per 1.73 m2. Although the event rate was not different between CKD and non-CKD patients during follow-up, it might be due to the small sample size in the present study. Estimated GFR can be wrong in individuals with creatinine generation and/or renal tubular creatinine secretion that differs widely from those average values for any important parameter, such as low muscle mass due to mutilations or low body mass, high muscle mass in athletes, or drug-inhibited tubular creatinine secretion. Any overestimation of serum creatinine implies an underestimation of true GFR. This bias is much greater for serum creatinine in the near-normal range than for serum creatinine in the high range, because of the nonlinear relationship of serum creatinine with GFR and the steepness of the slope between serum creatinine and GFR for serum creatinine in the near-normal range (17). Clinical Implications According to the findings of this study, the increased risk of ACS in CKD patients is due to the increased number of vulnerable plaques. Therefore, a reasonable treatment to reduce the risk in these patients would be to prevent the formation of vulnerable plaques or to stabilize them ag-

gressively, although we have only statins as an established medication to regress or stabilize vulnerable plaques.

Conclusions CKD was an independent risk factor of multiple coronary yellow plaques, suggesting that patients with CKD would have a higher risk of coronary events because they had more yellow plaques than patients without CKD. Acknowledgments These findings were in part presented as a poster in Cardiovascular Research Technologies (CRT) 2011, February 27 to March 1, 2011. Disclosures None.

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