The MASS-V Trial is an institutional project that the Heart Institute (InCor), Hospital das Clinicas, University of São Paulo designed to prospectively investigate 150 patients with multivessel coronary artery disease (CAD) with normal left ventricle ejection fraction (LVEF) and with a formal indication for CABG or PCI. Fifty patients will be operated on with cardiopulmonary bypass (CPB) and another 50 patients with the same arterial and ventricular conditions and also with a proper indication for myocardial revascularization will be operated on without the help of the CPB circuit. Another 50 patients with CAD and preserved ventricular function with a formal indication for percutaneous coronary intervention (PCI) with the use of intracoronary "stents” will be analyzed.
The inclusion criteria will determine which patients are eligible for which of the three procedures. Anginal symptoms must be stable and the LVEF preserved. The main steps of the procedures are shown in Figure 1. Exclusion criteria include the following: recent myocardial infarction (≤6 months); signs of manifest or suspected infections or rheumatologic disease activity; chronic renal failure (creatinine level >2.0 mg/dL); recent (≤ 6 months) pulmonary embolism or venous thromboembolism; not signing the consent form; contraindication for the use of glycoprotein IIb/IIIa inhibitors or CMR examination, for example, a person with a pacemaker or severe claustrophobia.
All patients will undergo CMR before and after surgical or percutaneous interventions to determine the presence or absence of myocardial necrosis complications after the procedure.
In addition, we will be evaluating the release of cardiac necrosis markers immediately before and after each procedure. The measurement of necrosis markers in the series will be conducted 6, 12, 24, and 36 hours after the percutaneous intervention. For the surgical procedures, dosage series will expand from 48 to 72 hours.
CMR protocol
The patients will be studied in a 1.5-T clinical MR scanner (Philips Achieva), and steady-state free-procession cine images will be acquired in 2 long-axis (2 and 4 chambers view) and 8 to 10 short-axis views of the left ventricle. A gadolinium-based contrast agent (Gadoterate meglumine Gd-DOTA, Guerbet SA, France) will then be injected intravenously (0.1 mmol per kilogram of body weight), and contrast-enhanced images will be acquired after a 5- to 10-minute delay with the use of an inversion-recovery segmented sequence. Contrast-enhanced images will be acquired in long- and short-axis planes identical to the cine images. Typical voxel size will be 1.6x2.1x8mm, with a reconstruction matrix of 528 and a reconstructed voxel size of 0.6 mm. The method for acquiring and analyzing CMR is standardized in our service and is reproduced according to conventional techniques [2, 8].
Delayed enhancement
Delayed enhancement of cardiac magnetic resonance will be performed with a phase-sensitive inversion recovery (PSIR) sequence (repetition time 6.1, echo time 3.0 ms, voxel size 1.6x2.1x8mm, flip angle 25o) following a 5-min time delay after the administration of 0.1 mmol/kg contrast agent (Gadoterate meglumine Gd-DOTA, Guerbet SA, France). Images will be acquired in two long-axis planes and in a short-axis stack covering the entire left ventricle. The inversion time will be meticulously adjusted throughout the acquisition to obtain optimal nulling of remote normal myocardium. The slice thickness at the apex will be reduced to 5 mm to avoid a partial volume effect [7].
CMR postprocessing and data analysis
All areas of late gadolinium-DTPA hyperenhancement will be quantified with a computer-assisted planimetry program - CMR42 v. (Circle Cardiovascular Imaging, Calgary, Canada) and interpreted by two experienced observers blinded to the interventional technique and biochemical data. When measurements are different, a third observer will perform a review and a consensus will be obtained.
Hyperenhanced pixels are defined as those with image intensities >2 SDs above the mean of image intensities in a remote myocardial region in the same image. Furthermore, we prospectively identified the site of any new hyperenhancement in relation to the implanted stent. Areas of new hyperenhancement that occur in the same short-axis image as the stent will be classified as adjacent to stent injury, whereas new hyperenhancement that occurs in the myocardium distal to the stent is deemed downstream injury.
Just as with a percutaneous intervention, hyperenhanced pixels will be defined as image intensities greater than two standard deviations above the mean intensities in a remote myocardial region in the same image. Preintervention and postintervention scans will be read side by side in both surgical techniques, with and without extracorporeal circulation.
Biochemistry
Blood samples will be collected from each patient for measurement of troponin I (TnI) and CK-MB mass immediately before PCI and 6, 12, 24, and 36 hours after the procedure. For patients undergoing coronary artery bypass surgery, on-pump or off-pump, these cardiac markers will be measured immediately before surgery and 6, 12, 24, 36, 48, and 72 hours after surgery.
The surgeon and clinical team will be blinded to the CK-MB or TnI data.
All the samples will be centrifuged at 3000 rpm for 20 minutes and analyzed within 2 hours after specimen collection. TnI and CK-MB analysis will be performed in an immunoassay analyzer (ADVIA Centaur, Siemens Health Care Diagnostics, Tarrytown, NY). According to the manufacturer, the lower limit of detection of TnI using a high-sensitivity kit, the Ultra kit, is 0.006 ng/mL, and the 99th percentile and MI reference limits are respectively 0.04 and 0.76 ng/mL. The assay precision, represented by the percentage coefficient of variation (%CV) is ≤ 10 % at 0.03 ng/mL.
The detection limit of the CK-MB mass kit is 0.18 ng/mL, and the cut off values at the 99th percentile, established by our laboratory, are 3.8 ng/mL for women and 4.4 ng/mL for men. The CVs for CK-MB mass, as specified by the manufacturer, are 3.91 % at 3.55 ng/mL and 3.61 % at 80.16 ng/Ml.
Statistical analysis
Values will be expressed as mean (±SD) or median (interquartile range) as appropriate. The paired-sample t test and the unpaired-sample t test will be used to compare means within the study group or between subgroups. χ
2 statistics with Fisher’s exact test will be used for comparison of discrete variables. Continuous variables that were not distributed normally will be compared with the Mann–Whitney U test, and correlation between such variables will be made with the Spearman rank test. Binary logistic regression will be performed to determine which clinical and angiographic parameters predict the likelihood of myocardial hyperenhancement. Multivariate logistical regression will be used to assess the relative contribution of various clinical and angiographic variables to the presence of new hyperenhancement after PCI or CABG. A probability value of <0.05 is considered statistically significant.
Trial outcomes
Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and left ventricle ejection dysfunction assessed by CMR.