Epicardial adipose tissue in patients with stable chest pain: Insights from the PROMISE trial

LETTER

Introduction

A growing body of evidence, primarily based on cohorts with low cardiovascular risk, suggests that epicardial adipose tissue (EAT), a metabolically active tissue surrounding coronary arteries, is associated with coronary artery disease (CAD) and adverse cardiac events (1,2). However, little is known about the predictive value of EAT in symptomatic patients with elevated cardiovascular risk. We investigated the relationship between EAT, traditional cardiovascular risk factors, CAD characteristics, and incident adverse events in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), a symptomatic cohort with increased cardiovascular risk (3).

Methods

We included PROMISE patients who underwent cardiac computed tomography (CT) and followed them for a median two years for adverse cardiac events (composite of death, non-fatal myocardial infarction, and hospitalization for unstable angina) (3). Local and central institutional review boards approved the study, and all patients provided written informed consent. Our dedicated core-lab measured EAT volume (indexed by body surface area –cm³/m²) and attenuation (HU) on non-contrast ECG-gated CT. We used a deep-learning-based system to segment EAT. The system consisted of two consecutive U-Nets to localize and segment pericardial sac, followed by an attenuation-based mask to render EAT (details provided in Figure 1A). Also, our core lab manually measured coronary artery calcium (CAC) score, CAD extent (segment involvement score; SIS), and presence of high-risk plaque features (HRPF: spotty calcium, positive remodeling, napkin ring sign, low attenuation plaque) using standard methods.

Figure 1. EAT and Cardiac CT Imaging.

Epicardial adipose tissue (EAT) segmentation and EAT distribution across categories of cardiovascular risk factors and coronary artery disease (CAD) characteristics. ASCVD, Atherosclerosis Cardiovascular Disease risk score; CAC, coronary artery calcium; CT, computed tomography; EAT, epicardial adipose tissue; HRPF, high-risk plaque features; HU, Hounsfield unit; IQR, interquartile range; SIS, segment involvement score.

Our statistical analysis compared EAT volume between men and women, elderly (≥65 years) and younger patients, across categories of CAC, and in those with 10-year atherosclerotic cardiovascular disease (ASCVD) risk score ≥7.5% vs. <7.5%, SIS ≥4 vs. <4, and HRPF present vs. absent. In time to event analysis, we tested the association between EAT and events unadjusted and adjusting for ASCVD risk.

Results

In 3,948 patients (60.6±8.3 years; 51% women), mean EAT volume and attenuation were 57.5±22.0 cm³/m² and −86.8±5.1 HU, respectively. Men presented with higher EAT volume and attenuation compared to women (p<0.05 for all, Figure 1B). The elderly and those with ASCVD ≥7.5% had more EAT but lower EAT attenuation compared to younger and those with ASCVD <7.5%.

Regarding CAD, EAT volume increased, and attenuation decreased proportionally to the CAC score (p<0.001 for both). Likewise, patients with SIS≥4 or HRPF had higher EAT volume and lower attenuation compared to those with <4 stenotic segments or absent HRPF (p<0.001 for all, Figure 1B).

Overall, 128 (3.2%) patients experienced events during a median follow-up of 26.1 (18.0–34.4) months. Greater EAT volume was associated with a higher relative hazard of adverse events (HR per increase of 10 cm³/m² EAT volume: 1.01; 95%CI: 1.00–1.15; p=0.036) in univariate analysis. However, this association attenuated after adjustment for the ASCVD risk (p=0.264). EAT attenuation was not associated with events (p=0.409).

Discussion

In patients with stable chest pain and increased cardiovascular risk, we found higher EAT volume in males, the elderly, and those with increased cardiovascular risk and advanced CAD (i.e., higher CAC score, SIS, and HRPF). Nevertheless, these observations did not translate into an association between EAT volume and adverse events beyond traditional cardiovascular risk factors.

In accord with Mancio et al. (1), a meta-analysis with ~20,000 asymptomatic, low-risk subjects from mostly large longitudinal studies with long-term follow-up (e.g., Framingham Heart Study (FHS), Multi-Ethnic Study of Atherosclerosis (MESA), Heinz Nixdorf Recall (HNR) study, Early Identification of Subclinical Atherosclerosis by Non-invasive Imaging Research (EISNER) study, and the Rotterdam study), our results demonstrated a strong relationship between EAT, cardiovascular risk factors, and extent of CAD. However, we did not find an independent association between EAT volume and adverse events.

In a symptomatic population, EAT may have low short-term prognostic utility due to many confounding elements such as clinical risk factors, presence of established CAD, and management strategy (e.g., medical therapy, revascularization) which are physician-dependent and may have varied between sites due to pragmatic design of the PROMISE trial. Moreover, PROMISE patients already had an indication for CTA, based on their symptoms and pretest probability. While longitudinal studies in asymptomatic cohorts have shown independent predictive prognostic value for deep-learning-derived EAT, independent of ASCVD risk score (2), the prognostic relationship may be attenuated for symptomatic patients undergoing CTA due to the reasons mentioned above.

We found no relationship between overall EAT attenuation and events. Thus, the cardiovascular risk may be better predicted by the local attenuation of EAT directly adjacent to the coronaries. As shown by others, pericoronary EAT attenuation has shown a strong association with cardiovascular events (4). The differences may be due to the local effects of EAT versus the global attenuation assessed in our study.

To conclude, our results show a limited short-term predictive value of EAT in symptomatic patients with increased cardiovascular risk. Further research is needed to identify factors influencing the relationship between EAT and adverse outcomes.