Methods

From March 2008 to February 2010, 246 patients with type 2 DM and subclinical atherosclerosis were evaluated. Of these 246 patients, 232 consented to undergo MSCTA. Subclinical atherosclerosis was assessed by carotid ultrasonography, and all the patients were classified into subgroups according to the carotid IMT or the presence of carotid plaque (CP). According to the joint European Society of Hypertension/European Society of Cardiology guidelines, subclinical atherosclerosis was defined as an abnormally increased IMT or the presence of CP. A carotid IMT >0.9 mm indicates an abnormally increased IMT. The presence of CP was defined as a focal increase in thickness of 1.5 mm or 50% of the surrounding IMT value. The American Diabetes Association criteria for the diagnosis of type 2 DM were used. An asymptomatic CAD status was confirmed using the Rose questionnaire for angina. To evaluate the status of subclinical atherosclerosis, patients who were definitively diagnosed with cerebrovascular and cardiovascular events were excluded. Additional exclusion criteria were known or suspected CAD, a history of coronary revascularization, treatment with antianginal medication, ventricular and supraventricular arrhythmias, contraindications for the use of iodinated contrast media, and renal failure (serum creatinine >1.5 mg/dl). The study protocol complied with the principles of the Declaration of Helsinki (revised in 2000) and was approved by the Internal Review Board of St. Mary’s Hospital. All subjects provided written informed consent before their participation in the present study.

The results of the physical examination, anthropometric measurements, blood pressure, laboratory data, and 12-lead electrocardiogram at rest were recorded for each patient. The blood samples were collected the morning after an overnight fast to measure the serum hemoglobin A1c, fasting plasma glucose, total cholesterol, triglycerides, and high-density lipoprotein cholesterol. All laboratory tests were performed using standard methods. Low-density lipoprotein cholesterol was calculated using the Friedewald formula: {total cholesterol − [high-density lipoprotein cholesterol + (triglyceride/5)]}. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation. Renal insufficiency was defined as an eGFR <60 ml/min/1.73 m ² . The albumin/creatinine ratio (ACR) was calculated for first-voided spot urine samples. The presence of diabetic nephropathy was defined as microalbuminuria (ACR 30 to 300 μg/mg creatinine) or overt proteinuria (ACR ≥300 μg/mg creatinine).

The measurements of the carotid IMT were performed using a high-resolution B-mode ultrasonography system (Logiq; GE Medical Systems, Milwaukee, Wisconsin) and an electrical linear transducer midfrequency of 7.5 MHz; each assessment was performed by an experienced radiologist who was unaware of all clinical information. During the ultrasound examination, the carotid IMT and the presence of CP were recorded. Initially, a region approximately 10 mm proximal to the bifurcation in the common carotid artery was identified. The IMT was defined as the distance between the leading edges of the first echogenic line and the second echogenic line in the far arterial wall. Three determinations of the IMT were measured in the near and far walls in the site of the greatest thickness of each common carotid artery. These 3 determinations were averaged and expressed as the mean IMT. The greater value among the mean IMTs was used for analysis.

A 64-slice multislice computed tomographic scanner (Lightspeed VCT 64; GE Healthcare) was used in the present study. The calcium score computed tomographic protocol was performed, followed by MSCTA using the scanning parameters. The effective radiation dose was 13.2 ± 1.21 mSV. Data acquisition was performed in a craniocaudal direction from the tracheal bifurcation to the diaphragm. The coronary artery calcium scores were measured for each calcified plaque using a dedicated software program (Smartscore, version 3.5; GE Healthcare, Milwaukee, Wisconsin). The calcium scores were calculated according to the method of Agatston et al. Coronary artery analysis was performed using a dedicated cardiac analysis software package (Advantage Windows, version 4.3; GE Healthcare, Milwaukee, Wisconsin). All angiograms were evaluated by 2 experienced radiologists who were unaware of the clinical history of the patients. Coronary arteries were divided into 17 segments according to the modified American Heart Association classification. Significant coronary artery stenosis was determined according to whether the lesion was obstructive, using a threshold of 50% luminal narrowing by MSCTA.

All the data are presented as the mean ± SD or percentages. Because the ACR and coronary calcium score were markedly skewed, log-transformed values were used for the analysis; however, the values were back transformed when presenting the results (for the ease of interpretation). For the study subjects with and without significant coronary stenosis, the significant differences of continuous and categorical variables were determined using an independent t test and chi-square test, respectively. Different models were constructed using multivariate logistic regression analyses by adjusting for confounding risk variables to identify an independent predictor of significant coronary stenosis detected by MSCTA. Receiver operating characteristic curve analyses was further performed to evaluate the diagnostic accuracy and the additive effect of adding an additional factor to the carotid IMT for predicting significant coronary stenosis. Analyses were performed using SPSS, version 16.0 (SPSS, Chicago, Illinois), and p <0.05 was considered statistically significant.

Results

The study group consisted of 232 patients with type 2 DM. The mean age of the subjects was 62 ± 10 years, and the mean body mass index was 25 ± 3 kg/m ² . The mean hemoglobin A1c level was 9 ± 2%, and the mean duration of DM was 12 ± 9 years. The mean carotid IMT was 1.31 ± 0.28 mm, and 125 patients (54%) had ≥1 CP. At least 1 segment of significant coronary stenosis was detected in 71 patients (31%) using MSCTA. Single-vessel disease was found in 29 patients, 2-vessel disease in 26 patients, and 3-vessel disease in 16 patients. No significant differences were found between the men and women.

A comparison of the clinical and biochemical variables of the patients with versus without significant coronary stenosis based on MSCTA is listed in Table 1 . The patients with significant coronary stenosis were more likely to be older and to have a longer duration of DM compared to patients who did not have significant coronary stenosis. Significant differences were detected in the log-transformed ACR, the degree of albuminuria and the proportion of renal insufficiency (eGFR <60 ml/min/1.73 m ² ; p for trend = 0.013) between the patients with and without significant coronary stenosis. As expected, a greater maximum carotid IMT and the presence of CP were associated with significant coronary stenosis. When those with normal eGFR and without albuminuria were considered the reference group, the age- and gender-adjusted odds ratios for significant coronary stenosis were increased in proportion to the degree of albuminuria even at the stratum of normal eGFR and in the stratum of reduced eGFR (<60 ml/min/1.73 m ² ; Table 2 ).

The continuous log-transformed ACR and the presence of diabetic nephropathy were each independently associated with significant coronary stenosis after adjusting for age, gender, BMI, duration of DM, family history of CAD, smoking status, and the presence of hypertension ( Table 3 , model 1). These associations remained significant even after controlling for hemoglobin A1c, fasting plasma glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and eGFR as continuous or categorical variables (model 2). Additional adjustment for the use of concurrent medications, including statins, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and insulin, had no significant effect on the results. The odds ratio of those predictors was 4.167 (95% confidence interval [CI] 1.497 to 11.599; p = 0.006) for the log-transformed ACR and 4.619 (95% CI 1.562 to 13.659; p = 0.006) for the presence of diabetic nephropathy in model 3. This significance was maintained after excluding 23 patients with overt proteinuria in the fully adjusted analyses.

Table 3

Independent associations between presence of albuminuria and significant coronary stenosis on multislice computed tomographic coronary angiography (MSCTA)

	Coronary Stenosis ≥50% (n = 71)
	p Value	Odds Ratio (95% CI)
Log albumin/creatinine ratio
Model 1	<0.001	2.659 (1.545–4.576)
Model 2	0.006	3.876 (1.462–10.278)
Model 3	0.006	4.167 (1.497–11.599)
Albumin/creatinine ratio (>30 μg/mg)
Model 1	0.003	2.883 (1.419–5.861)
Model 2	0.006	4.365 (1.530–12.449)
Model 3	0.006	4.619 (1.562–13.659)
Albumin/creatinine ratio (30–299 μg/mg) ⁎
Model 1	0.022	2.473 (1.138–5.371)
Model 2	0.029	3.419 (1.135–10.294)
Model 3	0.027	3.643 (1.154–11.498)

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