Study design
Study participants were consecutive patients without prior history of coronary artery disease (CAD) who were undergoing stress perfusion cardiac magnetic resonance (stress CMR) at our hospital between December 2019 and August 2021. They were referred to the cardiology clinics for suspected myocardial ischemia (such as chest pain) and subsequently had a diagnostic CT coronary angiography (CTA) demonstrating no evidence of significant coronary stenosis. A final cohort of 115 was established after excluding those with known CAD, including prior revascularization and/or myocardial infarction, primary cardiomyopathy (hypertrophic, dilated, and restrictive) and prior history of heart failure or severe valvular disease. This study complied with the Declaration of Helsinki and was approved by the local research ethics committee (2021-P2-418-01). All patients provided a written informed consent. Fig 1 shows the study flowchart and exclusion criteria of patients.
CMR parameters acquisition
CMR was performed on the MAGNETOM Prisma 3T MR scanner (Siemens Healthcare, Erlangen, Germany). All images were acquired using phased array surface coils during mild expiration and electrocardiographic triggering. Frist, patients were given ATP at an infusion rate of 0.16 mg/kg/min for approximately 2 min(heart rate increase≥10 bpm or systolic blood pressure decrease≥10 mmHg), followed by an intravenous administration gadolinium (injection rate: 3 to 4 mL/s, with a subsequent 30 mL saline flush at the same flow rate) to obtain the first-pass perfusion images using a T1 weighted fast gradient echo sequence for both scanners(TR/TE= 2.1/1.03ms, TI= 100 ms, temporal resolution = 155.7ms, flip angle = 10°; voxel size=1.9×1.9×8.0mm3). Three perfusion short-axis slice images (base, mid, apex) of the left ventricle were acquired. Then, the balanced steady state free-precession (bSSFP) cine images were acquired in multiple short-axis locations (every centimeter from base to apex) and 3 long-axis locations (2, 3, and 4 chamber) (TR/TE = 3.3/1.43ms, temporal resolution = 40ms, flip angle = 50°; voxel size=1.6×1.6×6.0mm3). Rest perfusion images were acquired in the same three short axis positions as the stress perfusion images at least 10 min after termination of ATP infusion. LGE images were acquired at least 8 min after the first gadolinium injection. The LGE parameters were: TR/TE = 5.2/1.96ms, TI = 300 ms, flip angle = 20°; voxel size=1.8×1.8×8.0mm3.
LV diastolic function assessment
For the image analysis, LV basic cardiac function parameters were measured by tracing the epicardial and endocardial borders of the short-axis cine images at end diastole and end systole automatically using post-processing software (CVI42; Circle Cardiovascular Imaging) and manually adjusted.
LV diastolic function was evaluated by the time-volume curve and CMR feature-tracking (CMR-FT) strain analysis allow quantification of LV global as well as regional diastolic function(19, 21, 22). The former was generated by continuously tracing endocardial borders during complete cardiac cycles automatically and adjusted manually and its first derivative curve to obtain LV peak filling rate (PFR) as Fig 2. The PFR was defined as maximal change in the LV volume per unit time (Δ volume/Δ phase), which was the LV maximum slope of the diastolic period. Diastolic dysfunction was characterized by decreased peak filling rate and prolonged time to peak filling rate (T-PFR)(23, 24). Last, myocardial deformation was evaluated by CMR-FT using CMR cine images as Fig 2. Indices reflecting LV diastolic function such as LV global peak longitudinal diastolic strain rate (LDSR), circumferential diastolic strain rate (CDSR) and radial diastolic strain rate (RDSR) were recorded(19, 21).
Coronary microvascular function assessment
Noninvasive quantification of coronary microvascular function was performed using stress CMR. Poor quality images or incomplete data were excluded from the analysis. The presence of ischemia was evaluated by segmental analysis of stress perfusion images, which were recorded in 16 segments (the apical segment is typically not in the field of view) and based on the American Heart Association 17-segment model(25). Inducible ischemia was defined as the presence of a stress perfusion defect and absence of matching LGE in≥1 segment that persisted for≥5 dynamics(15, 26, 27). Semi-quantitative myocardial perfusion was analyzed using the CVI42 software by manually tracing contours around the endocardium and epicardium to determine the left ventricular myocardial signal intensity (SI). CMR-derived myocardial perfusion reserve index (MPRI), defined as the ratio of stress/rest upslope normalized to the upslope of LV blood pool, is recorded(28, 29).
Statistical analysis
Continuous variables were presented as the means ± SD (standard deviation) and were as assessed for normality. Normally and non-normally distributed variables between groups were compared using independent t-test or non-parametric test (Manne-Whitney U-test or Kolmogorov-Smirnov test). Categorical variables were presented as percentages and were compared using chi-square test. The intraclass correlation coefficient (ICC) was used to determine inter- and intra-observer reproducibility. P< 0.05 was considered to be statistically significant. All statistical analyses were performed with SPSS (version 25.0; IBM SPSS Inc., Chicago, IL, USA).