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Coronary Ectasia Is Associated with Impaired Left Ventricular Myocardial Performance in Patients without Significant Coronary Artery Stenosis

Objectives: To determine both ventricular functions and tissue Doppler echocardiography (TDE)-derived myocardial performance index (MPI) in patients with coronary artery ectasia (CAE). Subjects and Methods: Twenty-five patients with CAE (13 men; mean age 57 ± 9 years) and 25 age- and sex-matched controls without CAE (8 men; mean age 54 ± 10 years) were enrolled in the study. Left and right ventricular functions were detected using conventional echocardiography and TDE. Results: Left ventricle-lateral wall (0.61 ± 0.17; 0.50 ± 0.10, p = 0.02), interventricular septum (0.66 ± 0.17; 0.52 ± 0.10, p = 0.007) and mean MPI (0.63 ± 0.15; 0.51 ± 0.09, p = 0.004) were increased in the CAE group compared to the control group. Right ventricular MPI was similar in both the CAE and control groups (0.58 ± 0.18; 0.52 ± 0.19, p > 0.05). Conclusion: The findings show that left ventricular MPI is different in CAE patients without obstructive coronary artery disease compared to the normal control group. Also in these patients, right ventricular MPI was similar to the control group.

knowledge, there has been no measurement of the myocardial performance index (MPI) to globally evaluate ventricular functions in patients with CAE. Equally important, right ventricular function, which is a prognostic indicator for most heart diseases [10,11] , has not been studied in patients with CAE. In this study, we aimed to determine both ventricular functions and TDE-derived MPI in patients with CAE.

Study Population
We enrolled 25 patients with CAE who underwent coronary angiography after having typical angina and/or who had CAE (13 males; mean age 57 8 9 years) and 25 age-and sex-matched controls without CAE who underwent elective coronary angiography (8 males; mean age 54 8 10 years). Approval was obtained from the institution's ethics committee for this study and all the enrolled patients gave informed consent. Patients with occlusive coronary artery disease, acute coronary syndrome, cardiopathies, congenital heart diseases, cardiac valve diseases, ventricular hypertrophy, branch blocks, ventricular pre-excitation and atrioventricular conduction abnormalities, severe systemic diseases or bad electrocardiographic windows were excluded from the study.

Coronary Angiography
Coronary angiography was performed on all the patients using the General Electric (GE) Innova 3100 (Milwaukee, Wisc., USA), with the standard Judkins technique without applying nitroglycerin. Two cardiologists (K.C. and A.C.) evaluated the coronary angiographies without knowing the clinical or routine biochemistry results of the patients. When there was no identifiable adjacent normal segment, the mean diameter of the corresponding coronary segment in the control group served as the normal value. The coronary flow rates of all subjects were measured using the thrombolysis in myocardial infarction (TIMI) frame count method as described for left anterior descending, circumflex, and right coronary arteries.

Echocardiography
Two-dimensional pulsed-wave Doppler and TDE were performed for all patients using a 2.5-MHz transducer (Philips, En-Visor C Ultrasound, Bothell, Wash., USA) in the left decubitus position during normal respiration according to the recommendations of American Society of Echocardiograpgy [12] . The diameters of the left ventricular and the thicknesses of diastolic walls were measured from the parasternal window with two-dimensional M-mode echocardiography. Left ventricular ejection fraction was calculated using the modified Simpson's method [13] . From the apical four-chamber view, Doppler recordings were obtained with the pulsed sample volume placed at the tip of the mitral leaflets. The peak early (E) and late (A) velocities, E-wave deceleration time (DT) and isovolumetric relaxation time (IVRT) were measured. Pulmonary venous flow was taken from the apical 4-chamber view by placing the pulsed-wave Doppler sample volume 1 cm into the right upper pulmonary vein. The venous peak systolic velocities (Ps) and the pulmonary peak diastolic velocity (Pd) were measured and Ps/Pd ratio was calculated.
Pulsed-wave TDE parameters were measured by an echocardiographic device with active TDE functions (Philips, EnVisor C Ultrasound). The filter settings and gains were adjusted to the minimal optimal level to reduce noise and eliminate the signals produced by the flows. A 3.5-mm sample volume was used. The TDE cursor was placed from the apical 4-chamber view on the mitral annulus opposite the septal and lateral walls and on the region where the tricuspid valve binds to the leaflet of the tricuspid annulus. A Doppler velocity range of -20 to 20 cm/s was selected and the velocities were measured online at a sweep of 100 mm/s. Peak systolic velocity (Sm), peak early (Em) and late (Am) diastolic velocities for each segment were measured and the Em/ Am ratio was calculated. The isovolumetric relaxation time (IRT) was measured from the end of Sm to the beginning of Em, the isovolumetric contraction time (ICT) was measured from the end of Am to the beginning of Sm and the time period of Sm was measured as the ejection time (ET). The MPI was calculated using the equation (ICT+IRT)/ET. The Sm, Em and Am values obtained from tricuspid annulus were used for the right ventricular MPI. The average of the Sm, Em and Am time intervals obtained from the mitral annulus-lateral and interventricular septum was used to calculate left ventricular mean MPI. All Doppler parameters were obtained by calculating the mean of 5 consecutive cycles. Echocardiography measurements were made by the same cardiologist (F.K.) who was blinded to the clinical and angiographic features of the patients. Intraobserver variability was assessed in 10 by repeating the measurements on 2 occasions (7-10 days apart) under similar basal status. Variability was calculated as mean percent error, which was derived as the difference between the 2 averaged data sets of measurements, divided by the mean.

Statistical Analysis
Continuous variables are expressed as mean 8 standard deviation (SD) and categorical variables are given as percentage. The Kolmogorov-Smirnov test was used to evaluate whether the distribution of variables was normal. A two independent sample t test or Mann-Whitney U test was used to compare continuous variables between 2 groups. The 2 test, 2 with continuity correction or Fisher's exact test were applied for the categorical variables when necessary. SPSS software 15.0 for Windows (Chicago, Ill., USA) was used for all statistical analysis. Calculated p values were considered statistically significant when they were ! 0.05.

Results
The intra-observer variability was ! 6%. The baseline characteristics of the CAE and control groups are shown in table 1 . Age, sex, blood pressures, heart rates, body mass index, fasting serum glucoses, lipid profiles, hypertension, diabetes mellitus, and coronary artery disease risk factors and current medications were similar (p 1 0.05).

Coronary Angiography
Two patients had CAE in all major coronary arteries including the left anterior descending, circumflex and right coronary arteries; 9 had only right CAE; 7 had only left anterior descending artery ectasia, and 2 patients had only circumflex artery ectasia; 3 patients had ectasia in the right coronary and the left anterior descending arteries, 1 patient had ectasia in the circumflex and left anterior descending arteries, and 1 patient had ectasia in the circumflex and right coronary arteries. All coronary arteries were normal in the control group. Coronary spasm, ectasia, plaque or stenoses were not observed in the control group.   V alues are means 8 SD or numbers with percentages in parentheses. ACEI = Angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; LAD = left anterior descending artery; LCx = left circumflex artery; RCA = right coronary artery; TFC = TIMI frame count; NS = not significant.

Discussion
The most common symptom of CAE is effort-induced angina and it can occur without significant coronary stenosis [6] . Demopoulos et al. [14] found that there is a similar incidence of angina pectoris in patients with isolated CAE compared to patients with significant coronary artery stenosis. Impaired coronary blood flow, which is defined as delayed antegrade dye filling, a segmental back flow, or deposition of dye in the coronary artery on coronary arteriography, were also postulated to be possible symptoms of myocardial ischemia in CAE patients [6,15] . In a study by Papadakis et al. [16] coronary flow velocity was measured using the TIMI frame count method and it was found to be lower in patients with CAE than both the obstructive CAD and control groups. The TIMI frame count method is a simple technique used to evaluate the quantitative index of coronary blood flow [17] . Kosar et al. [18] found a higher TIMI frame count in patients with CAE compared to the control group. Our study confirmed these findings as the TIMI frame count was significantly higher in patients     with CAE compared to the control group. Gulec et al. [19] used microvascular perfusion through the myocardial blush technique to evaluate and compare normal and ectasic segments of vessels in patients with isolated CAE and in controls. They found microvascular perfusion defects in ectasic segments that was hypothesized to affect left ventricular systolic and diastolic parameters and to reduce ventricular performance. In our study, left ventricular MPI of the CAE patients was significantly higher than the normal control group. This result confirms the findings of Gulec et al. [19] . Diastolic disorders in ischemic heart diseases are seen earlier than systolic dysfunctions [20] . Patients with coronary artery disease have reduced mitral E velocity and E/A ratio and ventricular relaxation delay compared to an age-matched age control group [21] . In our study, mitral E/A ratio of the CAE patients was significantly lower than the control group. Myocardial velocities obtained using TDE are considered to be the new parameters to evaluate left ventricular functions [22] . The Em/Am ratio and Em velocity are reduced in patients with disordered left ventricular relaxation [23] . In this study, the left ventricular Em/ Am ratio was significantly lower in the CAE group than the control group. Also, the right ventricular Em/Am ratio was significantly lower in the CAE group than the control group. Moreover, it has been found that Sm, Em and Am in coronary artery disease patients are related to mortality [24] . In our study, left ventricular interventricular septum Am velocity of the CAE group was significantly higher than the control group. Doppler-derived MPI is calculated by dividing the sum of the ICT and the IRT by the ET. MPI is a simple, reproducible, and noninvasive method to assess systolic and diastolic functions [25,26] . Also, MPI is related to left ventricular dysfunc-tion and clinical severity of heart failure and is a powerful parameter for the prognostic assessment of these patients [27] . It has been previously shown that increased Doppler-derived MPI is related to mortality in a variety of cardiac diseases [28] . Ozdemir et al. [28] have shown in their study that while Doppler-derived MPI is affected by preload and heart rate, TDE-derived MPI is not affected by either. In our study, left ventricular lateral wall, interventricular septum and mean MPI was significantly higher in CAE patients than the control group. However, right ventricular MPI was shown to be similar to the control group.
This study has some limitations. First, relatively few patients were included in this study, so the number of participating centers should be increased and the results should be confirmed with more comprehensive studies. Second, overall medications may influence the results between experimental and control groups. Previous studies show that ␤ -blockers, in addition to ACE inhibitors or ARBs, have beneficial effects on left ventricular remodeling [29] . Nearchou et al. [30] reported that ACE inhibitor therapy improved ventricle performance and Tei index during the early phase of inferior acute myocardial infarction. However, in our study, there was no significant difference in the medications.

Conclusion
Due to these findings, we propose that CAE is not a benign phenomenon occurring coincidentally during coronary angiography but that it is an important clinical situation requiring aggressive risk stratification even in the absence of obstructive coronary artery disease.