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1 Original Contribution The Impact of Glucose Control on Coronary Plaque Composition in Patients With Diabetes Mellitus Dong Ju Yang, MD 1, Moo-Sik Lee, MD 2, Wan Ho Kim, MD 1, Hyun Woong Park, MD 1, Ki-Hong Kim, MD 1, Taek-Geun Kwon, MD 1, Sang-Wook Kim, MD 3, Charanjit S Rihal, MD 4, Amir Lerman, MD 4, Jang-Ho Bae, MD, PhD 1 Abstract: Background. Patients with diabetes mellitus (DM) are known to have large necrotic core in their coronary plaque compared to non-dm patients. We assessed coronary plaque composition in patients with angina and with/without DM according to glucose control. Methods. Study subjects consisted of 114 non-dm patients, 14 well-controlled DM patients (hemoglobin A1c [HbA1c] <7.0%), and 37 poorly controlled DM patients (HbA1c 7%) who underwent virtual histology intravascular ultrasound (VH-IVUS) examinations of culprit lesions. Results. The DM patients had longer lesion length (20.2 ± 7.8 mm vs 17.0 ± 7.3 mm; P=.013) than non-dm patients. The plaque volume was highest in the poorly-controlled DM patients (188.9 ± 92.6 mm 3 ) compared with the non-dm patients (144.1 ± 92.3 mm 3 ; P=.011) and the well-controlled DM patients (151.7 ± 82.4 mm 3 ; P=.194). The well-controlled DM patients had less dense calcium (0.33 ± 0.14 mm 3 /mm vs 0.71 ± 0.60 mm 3 /mm; P=.020) and less necrotic core (0.71 ± 0.48 mm 3 /mm vs 1.30 ± 0.94 mm 3 /mm; P=.029) than the poorly-controlled DM patients and had similar amounts of dense calcium and necrotic core with non-dm patients, whereas fibrous and fibro-fatty volume showed no significant differences among the groups. Conclusion. Coronary plaque composition and plaque volume in well-controlled DM patients are similar to those in non-dm patients and both groups had less dense calcium and necrotic core volume than the poorly-controlled DM patients. These findings suggest hyperglycemia control is important in DM patients with angina. J INVASIVE CARDIOL 2013;25(3): Key words: intravascular ultrasonography, diabetes mellitus, coronary artery disease Diabetes mellitus (DM) is one of the major risk factors for both acute and chronic coronary artery disease and is associated with worse prognosis. 1,2 The association of DM with cardiovascular diseases and worse prognoses is likely due to rupture of coronary plaque and the generation of thrombus which is easily induced from the metabolic disorder caused by DM. 3,4 From the 1 Division of Cardiology, Heart Center, Konyang University Hospital, Daejon City, South Korea, 2 Department of Epidemiology, Konyang University Hospital, Daejon City, South Korea, 3 Division of Cardiology, Chung-Ang University Hospital, South Korea, and 4 Department of Cardiology, Mayo Clinic, Rochester, Minnesota. Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein. Manuscript submitted September 26, 2012, provisional acceptance given October 31, 2012, final version accepted November 9, Address for correspondence: Jang-Ho Bae, MD, PhD, FACC, Division of Cardiology, Heart Center Konyang University Hospital, 685 Gasuwon-dong, Seo-gu, Daejon City, South Korea, janghobae@yahoo.co.kr Coronary plaque in DM patients with stable angina is characterized by higher amounts of dense calcium and necrotic cores compared with non-dm patients. 5 However, there has been no report as to whether there are any differences of coronary plaque composition among different blood glucose control states in DM patients. In this study, we investigated the histological characteristics of coronary plaques according to the blood glucose control state in DM patients with stable angina who received coronary artery intervention. Hemoglobin A1c (HbA1c) has been an established marker of glycemic control and its value is used to guide diabetic therapy. 6 We regarded HbA1c as the surrogate for blood glucose state. We hypothesized that histological characteristics may be different according to the status of blood glucose in diabetic patients with coronary artery disease. Methods Subjects. The study population consisted of 331 consecutive patients who underwent virtual histology intravascular ultrasound (VH-IVUS) examination during percutaneous coronary intervention (PCI) from August 2006 retrospectively and whose data had been stored on digital video disc (DVD) at the Cardiovascular Center of Konyang University Hospital. We excluded 15 patients whose HbA1c values were unavailable and 151 patients with acute coronary syndrome, which can influence the coronary plaque composition. 7 Finally, a total of 165 consecutive patients with stable angina were selected as the subjects of this study. Subjects were divided into 3 groups: the patients without DM, the well-controlled DM patients with HbA1c level <7% and the poorly-controlled DM patients with HbA1c level 7%. The HbA1c level of 7% was based on American College of Cardiology/American Heart Association (ACC/ AHA) guidelines. 8 Intergroup comparisons and analyses were performed on the clinical findings and the VH-IVUS findings. This study was approved by the Institutional Review Board of Konyang University Hospital. Clinical patient information was obtained by analyzing their medical records and blood sampling for HbA1c, fasting blood glucose, and lipids on the fasting values measured at least 24 hours before the VH-IVUS examination. VH-IVUS analysis for each patient was performed on the culprit lesion before PCI. The culprit lesion was selected from the artery associated with ventricular wall movement disorder Vol. 25, No. 3, March

2 YANG, et al. Table 1. Baseline demographics. Non-DM DM (n = 114) HbA1c <7.0 HbA1c 7.0 P-Value a P-Value b (n = 14) (n = 37) Age (years) 61.3 ± ± ± Men 76 (66.7%) 10 (71.4%) 24 (64.9%) Cardiovascular risk factor Hypertension 59 (51.3%) 9 (64.3%) 24 (64.9%) Smoking 34 (29.6%) 5 (35.7%) 8 (21.6%) Prior myocardial infarction 10 (8.5%) 3 (21.4%) 4 (10.8%) DM duration (months) ± ± Treatment of diabetes OHA 11 (78.6%) 28 (75.7%).828 Insulin 1 (7.1%) 4 (10.8%).694 OHA and insulin 1 (7.1%) 1 (2.7%).466 No medication 3 (21.4%) 6 (16.2%).663 Imaged vessel LAD/LCX/RCA 58.1%/17.1%/16.2% 64.3%/7.1%/28.6% 51.4%/27.0%/16.2% Left main/others 7.7%/0.9% 0.0%/0.0% 5.4%/0.0% Multivessel disease 23 (41.1%) 4 (50.0%) 7 (58.3%) HbA1c (%) 6.4 ± ± FBS (mg/dl) 101 ± ± ± TC (mg/dl) ± ± ± HDL-C (mg/dl) 44.7 ± ± ± LDL-C (mg/dl) ± ± ± hs-crp (mg/dl) 0.42 ± ± ± LVEF (%) 66 ± 8 64 ± ± Creatinine (mg/dl) 1.01 ± ± ± DM = diabetes mellitus; FBS = fasting blood glucose; HDL-C = high-density lipoprotein cholesterol; hs-crp = high-sensitivity C-reactive protein; LAD = left anterior descending coronary artery; LCX = left circumflex coronary artery; LDL-C = low-density lipoprotein cholesterol; LVEF = left ventricle ejection fraction; MI = myocardial infarction; OHA = oral hypoglycemic agent; RCA = right coronary artery; TC = total cholesterol. a Non-DM versus HbA1c <7.0%; b HbA1c <7.0% versus HbA1c 7.0%. according to echocardiography, or the artery that had the most serious stenosis by IVUS if there was no ventricular wall movement disorder. DM was defined as hyperglycemia with a fasting blood glucose level over 126 mg/dl or the condition for which the patient was being treated with oral hypoglycemic agent or insulin. All subjects were given aspirin 100 mg and clopidogrel 300 mg and unfractionated heparin 120 IU/kg before the procedure, followed by daily aspirin 100 mg and clopidogel 75 mg. The coronary artery intervention was performed through the femoral artery or radial artery. Procedures in all subjects were performed successfully. VH-IVUS. After the injection of μg nitroglycerin, VH-IVUS examination was performed using a 20 MHz, 2.9 Fr monorail, electronic Eagle Eye Gold IVUS catheter (Volcano Therapeutics) and the chosen ultrasound device (Volcano Therapeutics). The VH-IVUS images were saved on a DVD-ROM for future analysis. The black and white IVUS analysis was performed in conformity with the directives of the AHA. 9 The spectral analysis of IVUS radiofrequency date was performed to identify the coronary plaque components using the commercial software (IVUS Lab; Volcano Therapeutics) by physicians blinded of the clinical patient information. Once the lesion was determined, the vascular lumen and adventitia were automatically determined. The border between the vascular lumen and adventitia were reconfirmed manually in all subsequent images. The border was determined only when both readers agreed. When their opinion differed, another doctor was asked to make judgment. Once the border has been determined, histological findings in all images are displayed using color codes and the numeric values of the area, vascular inside diameter, and outside diameter are displayed for each finding. Fibrous component is displayed in green, 138 The Journal of Invasive Cardiology

3 Glucose Control and Coronary Plaque Composition Table 2. Virtual histology intravascular ultrasound findings between the 3 groups. P- P- P- Non-DM DM (n = 114) HbA1c <7.0 HbA1c 7.0 P- (n = 14) (n = 37) Value a Value b Value c Value d Plaque volume (mm 3 ) ± ± ± Lesion length (mm) 17.0 ± ± ± Fibrous volume (mm 3 ) 52.7 ± ± ± Fibro-fatty volume (mm 3 ) 13.3 ± ± ± Dense calcium volume (mm 3 ) 7.4 ± ± ± <.001 Necrotic core volume (mm 3 ) 15.4 ± ± ± <.001 % Fibrous volume 59.4 ± ± ± % Fibro-fatty volume 12.9 ± ± ± % Dense calcium volume 9.1 ± ± ± % Necrotic core volume 18.4 ± ± ± cplaque volume (mm 3 /mm) 8.57 ± ± ± cfibrous volume (mm 3 /mm) 3.14 ± ± ± cfibro-fatty volume (mm 3 /mm) 0.82 ± ± ± cdense calcium volume (mm 3 /mm) 0.41 ± ± ± <.001 cnecrotic core volume (mm 3 /mm) 0.91 ± ± ± Data given as mean ± standard deviation. c = corrected (each volume divided by lesion length); DM = diabetes mellitus. a Non-DM versus DM; b Non-DM versus HbA1c <7.0%; c HbA1c <7.0% versus HbA1c 7.0%; d Non-DM versus HbA1c 7.0%. dense calcium in white, and necrotic core in red. In addition to the display of each image, the coronary plaque volume in the entire lesion and the percentage of volume for each component are also displayed. This method has an accuracy of 90%-95% and has already been used in comparative analysis of component findings. 10,11 Statistical analysis. All statistical data were indicated as means and standard deviations. The statistical data for the subject groups were processed using SPSS Statistics Program (version 11.0) and significance was considered when the P-value was less than.05. Intergroup differences were compared and analyzed using independent t-tests on continuous variables and chi-square test or Fisher s exact test on non-continuous variables. Sequential comparison among three groups was tested using ANOVA. Results Clinical characteristics. A total of 165 stable angina patients were included in the analyses, consisting of 114 non-dm patients, 14 well-controlled DM patients, and 37 poorly-controlled DM patients. The well-controlled DM patient group had higher fasting glucose levels than the non-dm patient group (124 ± 38 mg/dl vs 101 ± 15 mg/dl; P=.024), but lower than the poorly-controlled DM patient group (124 ± 38 mg/dl vs 153 ± 52 mg/dl; P=.008) (Table 1). Duration of DM was not different between the well-controlled DM group and the poorly-controlled DM group (134.9 ± months vs ± 88.1 months; P=.703). In the well-controlled DM group, the ratio of patients using an oral hypoglycemic agent, insulin, and no drug for treatment was 78.6% (n = 11), 7.1% (n = 1), and 21.4% (n = 3), respectively; in the poorly-controlled DM group, it was 75.7% (n = 28), 10.8% (n = 4), and 16.2% (n = 6), respectively, showing no significant differences between the groups. Gray-scale IVUS finding. Compared with non-dm group, the DM group had larger plaque volume (178.7 ± 90.7 mm 3 vs ±92.3 mm 3 ; P=.026) and longer lesion length (20.2 ± 7.8 mm vs 17.0 ± 7.3 mm; P=.013) (Table 2). Although the poorly-controlled DM group had larger plaque volume than the non-dm group (188.9 ± 92.6 mm 3 vs ± 92.3 mm 3 ; P=.011), the well-controlled DM group did not show significant differences in plaque volume compared with the non-dm group (151.7 ± 82.4 mm 3 vs ± 92.3 mm 3 ; P=.767). The well-controlled DM group had longer lesion length than the non-dm group (20.0 ± 6.5 mm vs 17.0 ± 7.3 mm; P=.155), but no significant difference compared with the poorly-controlled DM group (20.0 ± 6.5 mm vs 20.3 ± 8.3 mm; P=.895). When plaque volume was compensated with lesion length, no difference was shown between DM and non-dm groups (8.57 ± 3.71 mm 3 /mm vs 9.09 ± 3.79 mm 3 /mm; P=.411). The poorly-controlled DM group had larger corrected plaque volume than the non-dm group, but the difference was not statistically significant (9.60 ± 3.63 mm 3 /mm vs 8.57 ± 3.71 mm 3 / mm; P=.143) (Table 2). Vol. 25, No. 3, March

4 YANG, et al. Figure 1. Corrected fibrous, fibro-fatty, dense calcium, necrotic core volume in three groups. Corrected fibrous and fibro-fatty volume did not show significant differences in three groups. However, corrected dense calcium volume and necrotic core volume were significantly highest in the poorly controlled diabetes mellitus (DM) patient group. VH-IVUS findings. Fibrous volume and fibro-fatty volume in culprit lesions did not show significant differences between DM and non-dm groups. There were also no significant differences among the three groups when the DM group was divided into two groups according to the blood glucose control (Table 2). The DM group had larger dense calcium volume than the non-dm group (12.1 ± 10.2 mm 3 vs 7.4 ± 8.2 mm 3 ; P=.002). The well-controlled DM group had similar dense calcium volume compared to the non-dm group (6.6 ± 3.1 mm 3 vs 7.4 ± 8.2 mm 3 ; P=.719), and significantly lower dense calcium volume than the poorly-controlled DM group (6.6 ± 3.1 mm 3 vs 14.2 ± 11.2 mm 3 ; P=.016). However, % dense calcium volume showed no significant difference among the 3 groups (Table 2). The DM group had larger necrotic core volume than the non-dm group (23.1 ± 19.8 mm 3 vs 15.4 ± 13.2 mm 3 ; P=.004). The well-controlled DM group had similar necrotic core volume compared to the non-dm group (13.8 ± 9.6 mm 3 vs 15.4 ± 13.2 mm 3 ; P=.663) and significantly lower necrotic core volume than the poorly controlled DM group (13.8 ± 9.6 mm 3 vs 26.6 ± 21.6 mm 3 ; P=.038). However, % necrotic core volume showed no significant difference among the 3 groups (Table 2). When the plaque composition was compensated with lesion length, only corrected dense calcium volume was significantly higher in the DM group than in the non-dm group (0.61 ± 0.54 mm 3 /mm vs 0.41 ± 0.35 mm 3 /mm; P=.006). In the comparison among the three groups, corrected dense calcium volume and corrected necrotic core volume were significantly highest in the poorly-controlled DM group (Table 2; Figure 1). Linear regression analysis with variables including plaque volume, lesion length, dense calcium volume, necrotic core volume, corrected dense calcium volume, and corrected necrotic core volume showed that only necrotic core volume was associated with the poorly-controlled DM group out of VH-IVUS findings (ß: 0.275; 95% confidence interval, ; P<.001). Discussion The major findings in this study, in which the components of the culprit lesion in patients with stable angina were analyzed using VH-IVUS, are: plaque components and plaque volume in well-controlled DM patients were similar to those in 140 The Journal of Invasive Cardiology

5 non-dm patients; on the other hand, poorly-controlled DM patients had more necrotic cores and dense calcium than non- DM patients or well-controlled DM patients. Although the lesion length in the well-controlled DM group was longer than in the non-dm group, dense calcium volume and necrotic core volume were similar between these two groups. Nasu et al 5 reported that coronary plaque in DM patients among stable angina patients is greater in volume, dense calcium volume, and necrotic core volume compared to non-dm patients. A similar trend was shown in another study in patients with acute coronary syndrome compared with stable angina patients. 12 This suggests that the components of coronary plaque in DM patients may be similar to those in patients with acute coronary syndrome. However, there has been no report on the characteristics of coronary plaque in DM patients with different blood glucose level control status. The main causal factors of acute coronary syndrome are a large amount of necrotic cores in coronary artery, a thin fibrous membrane covering the plaque, and a large number of inflammatory cells. 13,14 Such histological morphology also suggests instability of coronary plaque. Moreover, calcification of the artery, which can be detected radiologically, is a predictor for future onset of cardiovascular disease in DM patients. 15 Patients with DM generally have 2-4 times higher morbidity and its associated fatality of cardiovascular disease compared with normal people. 16 Therefore, the ACC/AHA recommend that patients with acute coronary syndrome control their DM to HbA1c <7%. 8 High morbidity and its associated fatality of cardiovascular disease among DM patients is due to the onset of arteriosclerosis, its complications caused by the dysfunction of vascular endothelial cells and smooth muscle cells and the generation of thrombus DM patients may develop arteriosclerosis caused by inflammation and necrotic cores in coronary arteries, which, in turn, causes high risk of developing fragile plaque. 20 The efficacy of HMG-CoA reductase inhibitors (statins) in deferring the progress of fragile plaque has been proven and commercialized. 21 However, according to the results of this study, controlling the blood glucose level well in patients with DM may also contribute to the deferment of the progress of cardiovascular disease, because it causes the components of coronary plaque to become similar to those of stable angina patients. This study compared the characteristics of coronary plaque in patients with stable angina with well-controlled blood glucose level with those in poorly-controlled DM patients and non-dm patients, and suggests that blood glucose level control in DM patients may be an important factor for the stability of coronary plaque. Study limitations. The number of DM patients was relatively small compared with the number of non-dm patients, and there were only 14 patients with HbA1c <7%. However, this study used consecutive patients as the subjects and the distribution of subjects in the groups represented common frequencies of patients encountered in the clinical scene, which is clinically meaningful. Further study with a larger number of subjects should produce better results. Glucose Control and Coronary Plaque Composition Conclusion Coronary plaque composition and plaque volume in well-controlled DM patients are similar to non-dm patients and there was less dense calcium and necrotic cores than the poorly-controlled DM patients, although the lesion length in the well-controlled DM group was longer than in the non-dm group. Therefore, if blood glucose level in DM patients is well controlled to HbA1c <7%, dense calcium and necrotic core lesions in coronary plaque may be reduced. These findings suggest hyperglycemia control is important in DM patients with coronary atherosclerosis. References 1. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19): Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4): Biondi-Zoccai GG, Abbate A, Liuzzo G, Biasucci LM. Atherothrombosis, inflammation, and diabetes. J Am Coll Cardiol. 2003;41(7): Morgan KP, Kapur A, Beatt KJ. Anatomy of coronary disease in diabetic patients: an explanation for poorer outcomes after percutaneous coronary intervention and potential target for intervention. Heart. 2004;90(7): Nasu K, Tsuchikane E, Katoh O, et al. Plaque characterisation by Virtual Histology intravascular ultrasound analysis in patients with type 2 diabetes. Heart. 2008;94(4): Saudek CD, Brick JC. The clinical use of hemoglobin A1c. J Diabetes Sci Tecnol. 2009;3(4): Rodriguez-Granillo GA, McFadden EP, Valgimigli M, et al. Coronary plaque composition of nonculprit lesions, assessed by in vivo intracoronary ultrasound radio frequency data analysis, is related to clinical presentation. Am Heart J. 2006;151(5): Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-st-elevation myocardial infarction. J Am Coll Cardiol. 2007;50(7):e1-e Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS). A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2001;37(5): Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002;106(17): Nasu K, Tsuchikane E, Katoh O, et al. Accuracy of in vivo coronary plaque morphology assessment: a validation study of in vivo virtual histology compared with in vitro histopathology. J Am Coll Cardiol. 2006;47(12): Hong YJ, Jeong MH, Choi YH, et al. Plaque characteristics in culprit lesions and inflammatory status in diabetic acute coronary syndrome patients. JACC Cardiovasc Imaging. 2009;2(3): Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part I. Circulation. 2003;108(14): Virmani R, Kolodgie FD, Burke AP, et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20(5): Raggi P, Callister TQ, Cooil B, et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation. 2000;101(8): Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19): Moreno PR, Fuster V. New aspects in the pathogenesis of diabetic atherothrombosis. J Am Coll Cardiol. 2004;44(12): Creager MA, Luscher TF, Cosentino F, Beckman JA. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation. 2003;108(12): Breuer HW. Characteristics of atherosclerotic plaque in diabetics. Herz. 2002;27(2): Burke AP, Kolodgie FD, Zieske A, et al. Morphologic findings of coronary atherosclerotic plaques in diabetics: a postmortem study. Arterioscler Thromb Vasc Biol. 2004;24(7): Hong YJ, Jeong MH, Chung JW, et al. The effects of rosuvastatin on plaque regression in patients who have a mild to moderate degree of coronary stenosis with vulnerable plaque. Korean Circ J. 2008;38: Vol. 25, No. 3, March