Identification of vulnerable non-culprit lesions by coronary computed tomography angiography in patients with chronic coronary syndrome and diabetes mellitus

Background Among patients with diabetes mellitus (DM) and chronic coronary syndrome (CCS), non-culprit lesions (NCLs) are responsible for a substantial number of future major adverse cardiovascular events (MACEs). Thus, we aimed to establish the natural history relationship between adverse plaque characteristics (APCs) of NCLs non-invasively identified by coronary computed tomography angiography (CCTA) and subsequent MACEs in these patients. Methods Between January 2016 and January 2019, 523 patients with DM and CCS were included in the present study after CCTA and successful percutaneous coronary intervention (PCI). All patients were followed up for MACEs (the composite of cardiac death, myocardial infarction, and unplanned coronary revascularization) until January 2022, and the independent clinical event committee classified MACEs as indeterminate, culprit lesion (CL), and NCL-related. The primary outcome was MACEs arising from untreated NCLs during the follow-up. The association between plaque characteristics detected by CCTA and primary outcomes was determined by Marginal Cox proportional hazard regression. Results Overall, 1,248 NCLs of the 523 patients were analyzed and followed up for a median of 47 months. The cumulative rates of indeterminate, CL, and NCL-related MACEs were 2.3%, 14.5%, and 20.5%, respectively. On multivariate analysis, NCLs associated with recurrent MACEs were more likely to be characterized by a plaque burden >70% [hazard ratio (HR), 4.35, 95% confidence interval (CI): 2.92–6.44], a low-density non-calcified plaque (LDNCP) volume >30 mm3 (HR: 3.40, 95% CI: 2.07–5.56), a minimal luminal area (MLA) <4 mm2 (HR: 2.30, 95% CI: 1.57–3.36), or a combination of three APCs (HR: 13.69, 95% CI: 9.34–20.12, p < 0.0001) than those not associated with recurrent MACEs. Sensitivity analysis regarding all indeterminate MACEs as NCL-related ones demonstrated similar results. Conclusions In DM patients who presented with CCS and underwent PCI, half of the MACEs occurring during the follow-up were attributable to recurrence at the site of NCLs. NCLs responsible for unanticipated MACEs were frequently characterized by a large plaque burden and LDNCP volume, a small MLA, or a combination of these APCs, as determined by CCTA.


Imaging protocols and analysis
All CCTA scans were performed with a second-generation dual-source CCTA scanner (Somatom Definition Flash, Siemens Medical Solutions, Forchheim, Germany). Sublingual nitroglycerine and heart-rate control by betablocker for a target heart rate ≤70 beats/min were administered as appropriate. A non-contrast-enhanced cardiac CT scan was acquired to using standard techniques [1]. Afterwards, A contrast enhanced CCTA was performed with detector collimation of 2×128×0.6 mm, slice thickness of 0.6 mm, gantry rotation time of 280 ms, heart rate adaptive pitch of 0.2-0.5, tube current of 290 to 560 mAs/rotation and tube voltage of 80-120 kV. Contrast volume was 60-90 mL followed by a normal saline of 50 mL and was injected intravenously in an antecubital vein. Bolus tracking is used to synchronize the arrival of contrast in the coronary arteries and the initiation of the scan, and the region of interest (ROI) was set at the root of the ascending aorta. Data acquisition was initiated with a delay of 5 seconds after signal attenuation threshold (100 HU) was reached in ROI. Image scan was triggered from 30 % to 80 % of the R-R interval.
The CCTA images were analyzed at a core laboratory (Tianjin Chest Hospital, Tianjin, China) by experienced radiologists and cardiologists who were blinded to the clinical and other imaging data using semiautomated software (Autoplaque, version 2.5; Cedars-Sinai Medical Center, Los Angeles, Calif ) as previously described [2][3][4]. All segments ≥2 mm in diameter were analyzed and the maximal degree of coronary area stenosis was defined as <30%, 30-50% and >50% according to the CAD-RADS(TM) Coronary Artery Disease -Reporting and Data System [5]. All lesion with area stenosis ≥30% were identified in the present study.
Plaque components were quantified within the manually designated area using adaptive algorithms and automatically generated thresholds of calcified and non-calcified plaque (NCP). Low-density NCP (LDNCP) was defined as the portion of NCP with density levels ≤30 Hounsfield units. Manual adjustments were made if necessary. The quantitative analysis of lesions included area stenosis, absolute volumes of NCP, LDNCP and total plaque, remodeling index and lesion length. Plaque burden was defined as the plaque volume normalized to the vessel volume (plaque volume× 100%/vessel volume), expressed separately for each plaque component. Qualitative analysis of APCs was performed according to the definitions from previous studies [2][3][4][6][7][8] and established guideline [9], including area stenosis >50%, MLA <4mm 2 , plaque burden >70%, LDNCP volume >30mm 3 , positive remodeling (remodeling index>1.1), spotty calcification (diameter <3 mm in any direction, length of the calcium <1.5×vessel diameter, and width of the calcification <twothirds of the vessel diameter) and NRS (ring-like attenuation pattern with peripheral high attenuation tissue surrounding a central lower attenuation portion).
ICA was attempted through the radial or femoral artery. The angiographic images were acquired with a GE INOVA-2000 single-plane system at a cine rate of 30 frames/s. A minimum of 8 projections were obtained (minimum of 5 views for the left coronary artery system and minimum of 3 views for the right coronary artery system). Each coronary segment with a >1.5mm diameter was analyzed for the presence of coronary diameter stenosis by 3 experienced cardiologist who were unaware of clinical data and CCTA results. The severity of angiographic disease was also assessed by SYNTAX score.

Follow-up and study endpoints
Contact information including telephone number, e-mail address and home address were collected before CCTA. All patients were followed up until January 2022. Cardiac death was defined as any death caused by cardiac disease or for which no other cause could be found. Myocardial infarction was defined according to the Fourth Universal Definition of Myocardial Infarction [10].