Towards reference values of pericoronary adipose tissue attenuation: impact of coronary artery and tube voltage in coronary computed tomography angiography

Coronary artery disease (CAD) is caused by atherosclerosis of the coronary arteries. Prior studies showed that coronary inflammation plays an essential role in the development and progression of atherosclerotic plaque [1‐3]. An observational study demonstrated that invasively determined inflammatory changes of the coronary wall are present in early stages of CAD [4]. In the CANTOS trial, anti-inflammatory therapy reduced cardiovascular events, independent of lipid-lowering therapies [5, 6]. Efforts have been made to find a reliable non-invasive imaging parameter to detect coronary inflammation, focusing on adipose tissue [7‐10]. The amount of epicardial adipose tissue (EAT) has been quantified [11‐13], not only based on coronary computed tomography angiography (cCTA) but also based on coronary calcium scans or non-gated chest CTs [14, 15]. More recently, attention was focused on pericoronary adipose tissue (PCAT). Although PCAT is part of EAT, morphological and functional characteristics of PCAT are different from those of EAT. PCAT is directly affected by coronary inflammation, causing compositional changes of PCAT, while EAT is mainly affected by systemic conditions such as obesity [16]. A clinical pathology review suggested PCAT to be an independent risk factor for cardiovascular disease [17]. Antonopoulos et al indirectly evaluated coronary inflammation on cCTA around the RCA by measuring the fat attenuation index, equivalent to PCAT mean attenuation (PCAT_MA) [16]. They found a correlation between cCTA-derived PCAT_MA and adipocyte size or PCAT lipid volume in ex vivo PCAT histology. Additionally, PCAT and the coronary wall had a bidirectional communication, where inflammatory processes in the coronary vessel wall influenced PCAT composition via a paracrine pathway [16, 18]. In turn, PCAT influenced the coronary wall by secreted bioactive inflammation molecules [19]. In the presence of increased inflammation, higher CT attenuation of PCAT is expected [16].

Thus, PCAT could potentially be used as a non-invasive proxy to assess coronary inflammation based on routine cCTA imaging, and could offer valuable information for early diagnosis, treatment, and prevention of CAD. Several studies explored the diagnostic value of PCAT_MA in patients with plaques [20‐24]. However, studies including patients without plaque so far mainly focused on the healthy RCA in small cohorts of patients. Further standardization and validation, as well as reference PCAT_MA values in all three main coronary arteries without plaque, are needed before generalized clinical implementation can be considered. Reference values of PCAT_MA for healthy patients are necessary for the application in diseased patients because based on the healthy reference values clinicians may in the future be able to classify the coronary arteries into healthy or vulnerable vessels, even before the presence of plaque. Additionally, clinical cCTA scans are acquired at different tube voltages depending on patient characteristics and CT systems. Differences in tube voltage affect Hounsfield Unit (HU) values measured in different tissues. However, so far, no study has actually studied the magnitude of the effect of the tube voltage on PCAT. Potential future cutoff values in PCAT need to be seen in perspective of difference by tube voltage, and may need adjustment by kV setting.

The objectives of this study were to explore PCAT_MA reference values of three main coronary arteries in patients without plaque on cCTA, and to determine the influence of cCTA tube voltages and vessel analyzed on PCAT_MA measurement.

In this study, we investigated the PCAT_MA values of healthy coronary arteries and the influence of tube voltage. Our main results showed that the tube voltage of cCTA significantly influenced PCAT_MA values in patients without CAD, and that PCAT_MA differed slightly between the LAD, LCX, and RCA.

Although the presence of obstructive disease on cCTA is associated with worse outcomes, many myocardial infarctions originate from coronary segments without prior obstructive disease. Thus, the focus has shifted to the identification of segments at future risk of developing potentially vulnerable plaque [26]. Studies on PCAT_MA in diseased populations showed significant differences between diseased and non-diseased coronary arteries, and between flow-limiting and non-flow limiting stenosis [24]. Although results were statistically significant, these studies show, similar to the current study, limited absolute differences in PCAT values (± 5 HU). However, these studies show an increased accuracy for the prediction of hemodynamic significance of a lesion, especially in combination with other factors such as stenosis diameter. Further understanding of the PCAT parameter and the influence of scan protocol settings on this biomarker and its variability can help to determine limits of reliability around PCAT_MA values when comparing patients.

One of the main results of this study is that the use of different kV levels has considerable impact on PCAT_MA values. In clinical practice, cCTA acquisitions are acquired with varying kV levels. Higher kV voltages will inherently lead to higher PCAT_MA and EAT attenuation, unrelated to a pathophysiological process. Prior studies investigating the use of PCAT_MA used cCTA images obtained at 100 kV and/or 120 kV [16, 20, 21, 25]. However, lower kV acquisitions are becoming increasingly popular in order to reduce radiation and contrast medium volume. Recent results from the PROTECTION VI Study showed that low kV settings for cCTA (< 100 kV) are already applied in 14% of patients and this is only expected to increase [27, 28]. Our results showed significant differences between all kV levels except between 80 and 90 kV, and between 100 and 120 kV. The lack of difference in PCAT_MA between 100 and 120 kV is also reflected by the similar PCAT_MA results from previous studies investigating only those two levels. The differences in PCAT_MA between the other kV levels indicate that a kV-specific PCAT_MA cutoff should be used to discriminate healthy from diseased patients and perform accurate risk assessment. Determination of this cutoff fell outside the scope of this research. The current study provides reference values of PCAT_MA by kV setting in normal coronary arteries; future studies should investigate the PCAT_MA by kV in coronary arteries with plaque and/or stenosis, and evaluate the optimal cutoff values. To construct a kV correction factor, ideally the same patients would have to undergo repeated cCTA at different kV levels. The results also showed a positive relation between kV and EAT volume. This is likely mostly due to the fact that patients with higher BMI (and more intrathoracic fat) were usually scanned with higher kV to get better image quality. In view of the influence of kV on PCAT_MA analysis, it is recommended that for the longitudinal follow-up and comparison of cCTA-based PCAT_MA values, the cCTA is performed at equal tube voltage setting.

The majority of PCAT_MA studies about relationship with CAD focused on analysis of the RCA alone, while the LAD and LCX could provide additional information and increase the accuracy of outcome prediction [16, 21]. Our study focused on PCAT_MA measurements in all three coronary arteries, showing that PCAT_MA was slightly but significantly different between the LAD, LCX, and RCA. This difference could be caused by differences in anatomy and surrounding tissues, indicating that PCAT_MA values and corresponding cutoff values based on RCA measurements cannot be directly transferred to the other coronary arteries. Our study results showed that LAD had slightly but significantly lower PCAT_MA compared with the RCA and LCX. As is known in literature, atherosclerosis development also differs between the coronary arteries. The LAD is subject to atherosclerosis more often and at an earlier stage in comparison with RCA and LCX [29‐31]. The fact that LAD had a lower PCAT_MA is an important hypothesis-generating finding. This finding suggests that PCAT_MA could be related to vessel vulnerability for atherosclerosis. This hypothesis should be further investigated in pathophysiological and prospective clinical studies.

To analyze all three coronary arteries, an adjusted measurement method was used in our study. Previously, a measurement length of 40 mm was used [16, 21, 25] which was feasible for the RCA because it has fewer side branches and proximal variations than the LAD and LCX. To avoid influence of side branches, measurement length was reduced from 40 to 10 mm in this study. Results from our sub-study demonstrated no differences in PCAT_MA between our 10-mm methods and 40-mm method. PCAT_MA measurement width around the coronary could potentially affect measurement accuracy. Prior studies measured PCAT_MA using approximately 3 mm thickness (or equal to vessel diameter) around the coronary vessels [16, 20, 21, 25]. However, contrast enhancement of the lumen has been found to influence the HU values in the voxels adjacent to the luminal border [32]. To take this into account, we applied a 1-mm gap around the vessel wall. Thus, our study measured PCAT_MA using a more constrictive measurement width, making it more suitable for LAD and LCX measurements, and potentially more sensitive to inflammatory changes. Manual PCAT measurements using the method described here can be performed in a similar time span compared with manual EAT measurements. Fully automated software, as mentioned by some researchers [21], allows for PCAT_MA evaluation within 30 s, increasing the time efficiency of PCAT_MA analysis and enabling use in clinical practice.

While PCAT_MA and EAT both are measures of adipose tissue, they represent different processes [16]. PCAT_MA quantifies fat at the per-vessel level or per-lesion level as an indicator of coronary inflammation, while EAT provides a measure of the volume of the entire epicardial fat system as a marker for paracrine effects of fat. Thus, PCAT_MA may provide a more specific, focal assessment of coronary risk and vulnerability. PCAT_MA was shown to have additional diagnostic value with more precision and specificity compared with EAT measurements [33]. Studies found that PCAT_MA and FFR were related at the per-vessel level [20] and that PCAT_MA of RCA was able to assist in risk stratification of cardiovascular mortality [25]. The combined use of PCAT_MA, total plaque volume, and diameter stenosis has shown high diagnostic accuracy for prediction of hemodynamically significant coronary stenosis [24]. Interestingly, Goeller et al [21] found that changes in attenuation of adipose tissue in the pericoronary space were related to changes in plaque burden. These results suggest that these effects are associated with changes in PCAT specifically rather than adipose tissue in general.

Besides differences between kV levels and coronary arteries, our results show a slight but important difference in PCAT_MA between men and women that could not be explained by differences in kV distribution. Men are known to get CAD more frequently than women and at an earlier age [31]. The PCAT_MA difference between men and women follows the same trend. This finding deserves further exploration in a study with comprehensive cardiovascular risk factor assessment and more diverse range of coronary atherosclerosis. Sex-related differences in PCAT_MA could be caused by several factors. Men have a higher amount of EAT than women [34, 35], related to cardiovascular risk. There are sex-related differences in the regulation mechanism of pericardial adipokines [36] and in the physiological mechanism of adipose tissue [37]. Additionally, it could be that differences in sex-related hormones, higher low-density lipoprotein in male patients, and differences in risk factors impact PCAT_MA in men and women [38].

In conclusion, our results showed that PCAT_MA varied considerably by tube voltage in patients without plaque on cCTA, with minor differences in PCAT_MA between coronary arteries (LAD, LCX, RCA). cCTA kV setting needs to be taken into account when interpreting PCAT_MA values.