Between January 2007 and December 2012, 427 (4.1%) patients with CAE were selected from 10505 patients who underwent elective diagnostic coronary angiography in our center. After application of the exclusion criteria, the remaining 167 (1.6%) isolated CAE patients were designated the CAE group. During the same period, 150 age- and gender-matched controls with normal coronary arteries were consecutively selected. The indication for coronary angiography was the presence of typical angina pectoris or significant myocardial ischemia in noninvasive stress tests.

Exclusion criteria were as follows: acute coronary syndromes, history of alcohol consumption, high alanine and/or aspartate transaminase levels, presence of concomitant stenotic lesion (>25% stenosis), significant left ventricular hypertrophy (septal thickness ≥13 mm), hematologic disorders, acute or chronic infectious disease, hepatitis or previously known inflammatory/autoimmune disorders, renal dysfunction (serum creatinine ≥177 mmol/l), documented cancer, use of steroids, and significant valvular heart disease (moderate to severe for stenotic lesions or grade ≥2 for valvular regurgitation).

A detailed medical history and history of cardiovascular risk factors such as diabetes, hypertension and smoking were obtained from the study population. For each patient, body mass index (BMI) was calculated by the formula of weight (kg) divided by height (m)2. BMI was categorized as normal (≤25 kg/m2), overweight (25–30 kg/m2) or obesity (>30 kg/m2). Hypertension was considered to be present if systolic blood pressure was ≥140 mmHg or diastolic blood pressure was ≥90 mmHg or both, or if the individual was taking antihypertensive medication. Diabetes was defined as the use of antidiabetic therapy or a fasting plasma glucose level of ≥7 mmol/l (≥126 mg/dl) in at least two measurements. Family history of CAD was diagnosed if patients had a first-degree male relative <55 years of age or female relative <65 years of age with CAD. Patients who smoked before hospitalization were classified as smokers. Hyperlipidemia was defined as LDL cholesterol ≥3.4 mmol/l (≥130 mg/dl), triglycerides ≥2.26 mmol/l (≥200 mg/dl) or use of lipid-lowering drugs.

All patients gave their informed consent for participation in the study, which was approved by the local ethics committee.

Blood samples were drawn after a fasting period of 12 hours. Serum glucose, creatinine and lipid profile were determined by standard methods. Whole blood counts were made in a blood sample collected in dipotassium EDTA tubes with an automatic blood counter (Beckman Coulter Inc., CA, USA). Serum GGT levels were measured by the enzymatic calorimetric method using commercially available test kits with an AU640 auto-analyzer (Olympus, Japan). Normal values were defined as 0–50 U/l in our laboratory. In addition, other biochemical tests were performed using original kits with the Olympus autoanalyzer. Serum hs-CRP was measured by nephelometry using commercially available kits in accordance with the manufacturer's instructions (Beckman Coulter Array 360, Brea, CA, USA).

Using the Judkins technique, coronary angiography was performed with contrast agents without intracoronary nitroglycerin. Arteriograms were obtained in both right and left anterior oblique projection with caudal and cranial angulation for the left and right coronary system. Additional views were also obtained in patients with inadequate visualization. Images were recorded in digital format and stored for later analysis. Right anterior oblique view was used to evaluate ectasia for the left coronary system and left anterior oblique view for the right coronary artery. Evaluations were performed visually by two experienced angiographers blinded to each other's findings. Vessel diameter was calculated quantitatively in the event of disagreement concerning CAE. Each major coronary artery was subdivided into proximal, mid, and distal segments.

Coronary ectasia was defined as dilation exceeding 1.5 times the normal diameter of normal adjacent segments.1–3 If no normal adjacent segment could be identified, the mean diameter of the corresponding segment in the control group was taken as the normal value. If the coronary arteries had a normal appearance or no atherosclerotic plaques with ≥25% stenosis, they were regarded as normal. Patients with concomitant obstructive and ectatic lesions were not included in the study. CAE was defined as focal when involving one segment and as diffuse when involving two or more segments in a major coronary artery, and as severe when diffuse (≥2 segments) in ≥2 vessels.

Continuous variables were presented as mean ± standard deviation or median (interquartile range [IQR] of the 25th–75th percentiles of GGT and hs-CRP levels) and categorical variables as number (%). Comparisons between the groups were performed with the Student's t test, the Mann-Whitney U test and chi-square test or Fisher's exact test as appropriate. Gender-specific GGT tertiles were calculated in both groups, with GGT cut points of 18 and 24 U/l in men and 15 and 23 U/l in women delineating low, mid and top tertiles. Similarly, hs-CRP was categorized into low, mid and top tertiles (cut points of 1.53 and 2.56 mg/l). After univariate analyses had been performed for CAE, binary logistic regression analysis was performed to identify independent variables associated with the presence of CAE. Confounders which had significance at the p≤0.15 level were entered into the regression analysis. They were hypertension, diabetes, obesity, triglycerides, uric acid, GGT, hs-CRP and platelet count. Odds ratios (OR) and 95% confidence intervals were calculated. The correlation between GGT and CRP levels was evaluated by Pearson correlation analysis. A p value of <0.05 was considered significant. All analyses were performed using SPSS 12.0 (SPSS Inc., Chicago, Illinois, USA).

Previous small studies have reported different frequencies of major risk factors for atherosclerosis in isolated CAE patients.2,3,7–11 In our study, there was a predominance of male gender (58%) in CAE patients, as in previous studies.2,8,11,18,21 The proportion reaches 85% in some studies.7,9

Among risk factors, hypertension and obesity were slightly more prevalent in isolated CAE patients in the present study, whereas the rate of diabetes was lower in CAE patients. Other factors were at similar percentages. Only one study has shown a higher frequency of hypertension in CAE patients,11 in contrast to other studies.2,3,7–10,18,19 Similarly, hyperlipidemia has been reported to be more common in CAE patients in one study9 but not in others.2,3,7,8,10,11,18,19 Both high8 and low7,9 prevalences of smoking have also been documented in patients with CAE. We consider that these conflicting results may be mainly due to the selection of the control group from patients undergoing coronary angiography, and the small size of the studies. We constituted the control group from patients with normal coronary arteries, whereas some studies selected patients with CAD as the control group.7,9

Interestingly, previous studies8,10 reported an inverse association between CAE and diabetes, as in our study, in which diabetes independently decreased the likelihood of CAE (OR: 0.44). However, this inverse association was not seen in several other studies.3,4,7,9,11,18 There are two potential explanations for this association: in diabetic patients, compared with non-diabetic patients, negative arterial remodeling is seen more frequently in the coronary arteries during the progression of atherosclerotic plaques22; and consequently obstructive CAD can be found more commonly in diabetic patients.23

We found that obesity independently increased the likelihood of CAE (OR: 2.84, p=0.04). Such an association was not present in previous studies.2,3,7–11,18,21 We think that this finding may be the result of compensatory enlargement due to increased body weight, because we did not routinely measure the diameters of the ectatic vessels and did not index them to body surface area.

In humans, GGT is responsible for extracellular catabolism of glutathione, an antioxidant.12 There is evidence that GGT triggers oxidative stress within atherosclerotic plaque and promotes the atherosclerotic process by means of LDL oxidation.12–14 This finding has been supported by large epidemiologic studies15,16 in which GGT level is independently associated with cardiovascular disease and mortality. Furthermore, it is an independent predictor of fatal and non-fatal cardiac events in patients with documented CAD.22

Two recent studies have reported that GGT levels are increased in patients with isolated CAE compared to controls with normal coronary arteries, but are not associated with the severity of CAE.18,19 Their sample size was small, including only 88 and 45 CAE patients. In our larger study, CAE patients had a higher level of GGT compared with controls. Moreover, GGT was independently associated with the presence of CAE as well as with the severity of CAE. We think that GGT may have a prognostic value for CAE, as also reported for atherosclerotic CAD.24

Inflammation plays a key role in the atherosclerotic process and CRP can predict future cardiovascular events in men and women at risk.4 hs-CRP has been documented to be elevated in patients with CAE in some studies5,6 but not in others.25,26 However, these studies had small patient populations. In the present study, hs-CRP levels were higher in CAE patients than controls, and independently associated with the presence of CAE.

Previous studies showed an association of GGT with CRP.13,27,28 GGT can act as a proinflammatory protein in atherogenesis27 and is associated with atherosclerotic risk factors including obesity, dyslipidemia, metabolic syndrome, hypertension and diabetes.16,17,28 There was a moderate link between GGT and hs-CRP in our study. This evidence suggests that GGT and CRP may reflect chronic occult inflammation in CAE patients.

In addition, some small studies reported similar platelet counts in CAE and control groups,29–31 but in contrast, one large study reported significantly lower platelet counts in CAE patients than in controls.32 Similarly, in our larger study, platelet count was lower in the CAE group. We consider that these conflicting results may be mainly due to the small size of the studies.

The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).

The authors declare that they have followed the protocols of their work center on the publication of patient data.

The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.