Coronary computed tomography angiography (CTA) is a first-line investigation in suspected coronary artery disease. Further to the detection of luminal stenosis, coronary CTA can characterize distinct high-risk plaque (HRP) features associated with an increased risk of adverse events.
Coronary inflammation, a key driver of atherosclerotic plaque formation and rupture, inhibits lipid accumulation in adjacent adipocytes, resulting in a 3-dimensional gradient in the aqueous or lipid content of the perivascular adipose tissue. These inflammation-induced changes can be quantified as perivascular attenuation gradients using the coronary CTA–derived Fat Attenuation Index (FAI). Perivascular FAI has incremental prognostic value beyond traditional risk factors, as shown in the CRISP-CT (Cardiovascular Risk Prediction using Computed Tomography) study. However, it is unclear whether the FAI provides incremental value to HRP.
We now present a post hoc analysis in which we stratify the CRISP-CT study population based on: 1) the presence (HRP+) or absence (HRP–) of HRP (defined as ≥1 of the following: positive remodeling, low-attenuation plaque, spotty calcification or napkin-ring sign anywhere along the coronary tree); and 2) high versus low perivascular FAI (Figure 1A). Vessel-specific perivascular FAI mapping was performed around the proximal right coronary artery and left anterior descending artery using the CaRi-HEART algorithm as previously described, and the study population was split in high (FAIhigh) versus low (FAIlow) groups based on validated FAI thresholds. As per our prior work, the left main stem was not analyzed because of its variable length and anatomy. The study was approved by the local Institutional Review Boards (Cleveland Clinic Institutional Review Board 17-915 and ethics committee of the Friedrich-Alexander University Erlangen-Nürnberg).
Among 3,912 patients undergoing clinically indicated coronary CTA (mean age 55.7 ± 13.7 years, 1,608 [41.1%] women) followed over 5.3 ± 2.1 years, 74 cardiac deaths were recorded. For a right coronary artery FAI cutoff of –70.1 Hounsfield units (5), FAIhigh/HRP+ patients had a 7.3-fold higher adjusted risk of cardiac mortality compared with the FAIlow/HRP– reference group after adjustment for age, sex, hypertension, hypercholesterolemia, diabetes mellitus, smoking, epicardial obesity, and modified Duke Coronary Artery Disease Index group (Figure 1B). A higher risk was also seen among FAIhigh/HRP+ patients (hazard ratio [HR]: 7.33; 95% confidence interval [CI]: 3.22 to 16.67; p < 0.001) and FAIhigh/HRP– patients (HR: 5.65; 95% CI: 2.65 to 12.03; p < 0.001) compared with the FAIlow/HRP+ group. Similar trends were observed when stratifying the patient population based on the perivascular FAI around the left anterior descending artery, for a cutoff of –79.1 Hounsfield units (for FAIhigh/HRP+ patients, HR: 5.29; 95% CI: 2.10 to 13.32; p < 0.001; for FAIhigh/HRP– patients, HR: 3.92; 95% CI: 1.69 to 9.23; p < 0.001; for FAIlow/HRP+ patients, HR: 0.56; 95% CI: 0.14 to 2.24; p = 0.42) (reference: FAIlow/HRP–).
In a sensitivity analysis of 2,040 patients from the Cleveland subcohort (mean age 51.6 ± 14.0 years, 914 [44.8%] women) with available data on nonfatal myocardial infarction, the HR (vs. FAIlow/HRP– patients) for a composite endpoint of cardiac mortality and nonfatal myocardial infarction (n = 65 events over a mean follow-up of 4.47 ± 2.28 years) was 5.58 for FAIhigh/HRP– patients (95% CI: 2.87 to 10.83; p < 0.001), 3.59 for FAIhigh/HRP+ patients (95% CI: 1.56 to 8.27; p = 0.003), and 0.83 for FAIlow/HRP+ patients (95% CI: 0.38 to 1.80; p = 0.64). Finally, in a subgroup analysis of 1,415 patients with coronary artery calcium scoring, FAIhigh/HRP– remained associated with a significantly higher cardiac mortality risk (HR: 8.45; 95% CI: 1.63 to 43.70; p = 0.01) when compared with FAIlow/HRP– after further adjustment for coronary artery calcium, highlighting the value of FAI mapping in the HRP– population.
Our hypothesis-generating analysis highlights a striking improvement in risk stratification when FAI is added on top of HRP features in routine coronary CTA interpretation. In the presence of FAIlow, HRP features are not associated with increased cardiac risk, while in the presence of FAIhigh, HRP features flag a particularly high-risk group of patients. Future studies will focus on the mechanisms underlying these associations by exploring links with adverse plaque events (i.e., erosion vs. rupture) while also adjusting for quantitative HRP metrics (i.e., low-attenuation plaque burden).
In summary, by detecting early signs of coronary inflammation that precede the development of atherosclerotic plaques, FAI may identify the “vulnerable” patient prior to the development of “vulnerable plaques.” Including perivascular FAI in the routine interpretation of coronary CTA could provide new opportunities for personalized risk management in primary and secondary prevention.