Study Population
Consecutive patients over 18 years old with suspected or documented CAD referred for adenosine stress CMR between May 2011 and December 2014 were enrolled (Figure 1). Documented CAD was defined using (i) history of MI, (ii) abnormal stress test, (iii) presence of significant CAD on coronary angiography (>70% stenosis of three vessels or >50% stenosis of the left main coronary artery), and (iv) history of coronary revascularization including percutaneous intervention or coronary artery bypass graphing. Patients with a diagnosis of recent ACS (<6 months) were excluded due to dynamic change of ECG in this population. Patients with unreadable ECG or poor CMR image quality were also excluded. After exclusion, the group of patients with suspected CAD (Cohort A) were analyzed to determine the diagnostic value of resting ECG, while Cohort B patients that included those with documented CAD (prior CMR) were analyzed to assess the prognostic role of ECG (Figure 1). The study was done in accordance with the Declaration of Helsinki. The institutional ethics committee (Siriraj Institutional Review Board [SIRB], Faculty of Medicine Siriraj Hospital, Mahidol University) approved this retrospective study and waived the need for additional written informed consent.
ECG Data
Twelve-lead ECG was obtained on the CMR date as a routine protocol for adenosine stress CMR. Each ECG was reviewed by two trained cardiologists and discordant results were adjudicated by a senior cardiologist.
ECGs were coded according to the Minnesota Code (MC) and categorized into three groups as major, minor and no abnormalities based on the MC and according to previous publications (10-13). Criteria for major ECG abnormalities were any of the following: Q-QS wave abnormalities (MC 1-1 to 1-2-8); left ventricular hypertrophy (LVH) (MC 3-1); complete bundle branch block or intraventricular block (MC 7-1-1, 7-2-1, 7-4 or 7-8); atrial fibrillation (AF) or atrial flutter (MC 8-3); or major ST-T changes (MC 4-1, 4-2, 5-1 and 5-2). Criteria for minor ECG abnormalities were minor ST-T changes (MC 4-3, 4-4, 5-3 and 5-4) or minor/isolated Q waves defined as MC 1-3 that are not codable as MI in the absence of any other major Q waves (10, 12). Patients with both major and minor abnormalities were classified as having major abnormalities. Patients without minor or major ECG abnormalities were classified as having no ECG abnormality.
CMR Protocol (14, 15)
A CMR study was performed to assess cardiac function, myocardial perfusion and late gadolinium enhancement (LGE) using a 1.5 Tesla Philips Achieva XR scanner (Philips Medical Systems, Best, The Netherlands).
The cardiac functional study was performed by acquiring the images using a steady-state free precession (SSFP) technique in a vertical long axis, 2-chamber, 4-chamber and multiple slice short-axis views. Parameters for cardiac function were echo time (TE) 1.8 milliseconds (ms), repetitive time (TR) 3.7 ms, number of excitations 2, field of view (FOV) 390 x 312 mm, matrix 256 x 240, reconstruction pixels 1.52 x 1.21, slide thickness 8 mm and flip angle 70 degrees.
The myocardial first-pass perfusion study was performed by injection of 0.05 mmol/kg of gadolinium contrast agent (Magnevist, Bayer Schering Pharma, Berlin, Germany) at a rate of 4 ml/s immediately after a 4-minute infusion of 140 mcg/kg/min of adenosine. Three short-axis slices of basal, mid and apical left ventricular (LV) levels were acquired using an ECG-triggered SSFP, inversion-recovery, single-shot, turbo gradient-echo sequence. Image parameters were TE 1.32 ms, TR 2.6 ms, flip angle 50 degrees, slice thickness 8 mm, FOV 270 mm and reconstructed FOV 320 mm.
LGE images were acquired approximately 10 minutes after an additional bolus of gadolinium (0.1 mmol/kg, rate 4 ml/s) by the 3D segmented-gradient-echo inversion-recovery sequence. LGE images were acquired in multiple short-axis slices at levels similar to the functional images, long axis, 2-chamber and 4-chamber view. Parameters for LGE study were TE 1.25 ms, TR 4.1 ms, flip angle 15 degrees, FOV 303 x 384 mm, matrix 240 x 256, in-plane resolution 1.26 x 1.5 mm, slice thickness 8 mm and 1.5 sensitivity-encoding factor.
Image Analysis (15, 16)
Standard LV volumes, mass and ejection fraction (EF) were quantitatively measured from the stack of short-axis SSFP cine images.
The perfusion and LGE images were analyzed using visual assessment and consensus by two CMR-trained physicians blinded to clinical and follow-up data. Segmentation of each slice was performed according to the recommendation of the American Heart Association (17). Perfusion images were read, and each of the 16 segments was visualized (segment-17 at the apex was not visualized). Inducible ischemia was defined as a subendocardial perfusion defect that (i) persisted beyond peak myocardial enhancement and for several RR intervals, (ii) was more than two pixels wide, (iii) followed one or more coronary arteries, and (iv) showed absence of LGE in the same segment (16). Dark-banding artifacts were recorded if an endocardial dark band appeared at the arrival of contrast in the LV cavity before contrast arrival in the myocardium (16). LGE images were also analyzed using visual assessment. LGE was considered present only if confirmed on both the short-axis and at least one other orthogonal plane (16).
Clinical Follow-up
Follow-up data were collected from clinical visits and medical records. Clinical event adjudication was completely blinded to clinical and CMR data. Patients were followed up for MACE. MACE was defined as the composite outcomes of cardiac mortality, nonfatal MI, hospitalization for unstable angina, hospitalization for heart failure and late coronary revascularization (>180 days after CMR). Need for revascularization therapy within 180 days after the CMR was considered to be triggered by the CMR results and therefore censored from analysis. Cardiac mortality included death resulting from acute MI, heart failure, sudden cardiac death, or death due to complications in cardiac procedures (18).
Statistical Analysis
Statistical analyses were performed using IBM SPSS Statistics for Windows version 20.0 (IBM Corp., Armonk, NY, USA). Continuous variables with normal distribution were presented as mean ± standard deviation (SD), and continuous variables with non-normal distribution were presented as median and interquartile ranges. The normality of the distribution of variables was examined by the Kolmogorov-Smirnov test. Categorical variables were present as absolute numbers and percentages. Normally distributed continuous data of multiple (>2) groups were compared using one-way analysis of variance. Non-normally distributed continuous data of multiple (>2) groups were compared using the Kruskal-Wallis test. Continuous variables between two groups were compared using the Student’s unpaired t-test or Mann-Whitney U test. Categorical data were compared by the chi-squared test or Fisher’s exact test, as appropriate.
To analyze the predictors of myocardial ischemia, a Cox-regression analysis was performed to assess univariable predictors from baseline characteristics and ECG. Variables with a p-value <0.05 on univariable analysis were entered into the multivariable analysis. The incremental value of ECG in predicting myocardial ischemia was assessed by comparing the area under the receiver operating characteristic (ROC) curves for the DF model and clinical model of CAD consortium with and without the addition of ECG.
Kaplan-Meier plots were used to compare the proportion of patients in each group who had an event during follow-up. The log-rank test was used to compare groups on the Kaplan-Meier analysis. To analyze the predictors of MACE, a Cox-regression analysis was performed to assess univariable predictors from baseline characteristics and CMR parameters. Variables with a p-value <0.05 on univariable analysis were entered into the multivariable analysis. To assess the incremental prognosis values of multiple major ECG abnormalities, global chi-square values were calculated after adding predictors in the following order: clinical, numbers of major ECG abnormalities (1, 2 and more than 2 findings).
The hazard ratios (HRs) and 95% confidence intervals (CIs) of the outcomes were calculated, with a p-value <0.05 considered statistically significant.