Coronary plaque in the fourth dimension: associating coronary computed tomography plaque components and the time to acute coronary syndrome 

This editorial refers to ‘Early versus late acute coronary syndrome risk patterns of coronary atherosclerotic plaque’, by I. J. van den Hoogen et al., https://doi.org/10.1093/ehjci/jeac114.

Cardiovascular disease remains the leading cause of mortality in this country and acute coronary syndrome (ACS) one of its key contributors.¹ The presence of coronary artery disease (CAD) by any imaging modality increases the risk for ACS, with incrementally higher ACS risk with obstructive disease.^2,3 Identification of the exact coronary lesion that will result in ACS has been elusive such that the focus has been on identifying the vulnerable patient and less on the vulnerable plaque. More recently, three-dimensional coronary plaque analysis with coronary computed tomography angiography (CCTA) has been refined to allow for accurate non-invasive quantitation of plaque burden and various plaque components. CCTA data from observational studies demonstrated that increasing plaque burden, especially non calcified plaque, significantly increases an individual’s risk for future ACS.^4,5

In this issue of EHJ, van den Hoogen and colleagues⁶ as part of the ICONIC case–control study evaluated the associations of quantitative CCTA plaque analysis on subsequent ACS, specifically evaluating patients that experienced a subsequent early (<90 days) or late (>90 days) ACS. They also supported their findings with a validation cohort from the PARADIGM study with the primary outcome of major adverse cardiac events (MACE). The authors compared plaque components between patients with early and late ACS as patient-level analysis (primary endpoint). The authors also completed numerous secondary analyses that included a lesion-level analysis of culprit lesions where a single culprit lesion per patient was determined by invasive coronary angiography at the time of the ACS event and co-registered to the baseline CCTA. The plaque components at this culprit lesion, i.e. the ‘culprit lesion precursors’ were then compared between early and late ACS patients and over time (between-patient analysis). They also analysed the associations of plaque burden and plaque components between culprit and non-culprit lesions within a specific patient and their correlation with ACS timing (within patient analysis). The authors reported that the early ACS patient cohort had a greater non-calcific plaque volume, more obstructive CAD, higher maximal diameter stenosis, and higher maximal cross sectional plaque burden than the late ACS cohort. When comparing culprit lesion precursors between different patients (the between-patient lesion-level analysis), patients with early ACS had higher maximal stenosis and total plaque volume, but there were no other differences in plaque components between early and late ACS cohorts. When restricted only to proximal coronary segments, patients with early ACS had higher combined burden of fibrofatty and necrotic core plaque volume compared with patients with late ACS. In the within-patient lesion-level analysis, there was a higher odds of having early ACS with higher burden of plaque and all measured plaque components compared with non-culprit lesion precursors. However, only fibrofatty and necrotic core plaque volumes and high-risk plaque measures were statistically different between patients without ACS and patients with early or late ACS in an exploratory analysis.

This study largely fits with our histopathologic understanding of coronary atherosclerosis, in which increasing atherosclerotic plaque and higher lipid pool and necrotic core volumes are associated with advanced-stage atheroma, unstable plaque, and a higher propensity towards ACS.⁷ These associations are further supported by recent CCTA plaque studies. In the SCOT-HEART population of patients presenting with acute chest pain syndrome and who underwent CCTA, investigators found that more plaque on CCTA, especially low-attenuation (necrotic core) plaque, conferred an up to 4 times higher risk of ACS during a 4.7 year follow up.⁴ Nadjiri et al.⁸ similarly found that CCTA low attenuation plaque composition had the strongest association with MACE, including ACS. The CAPIRE trial found the burden of non-calcified plaque to be the best discriminator for future MACE over traditional risk factors.⁹ These studies taken in sum help solidify not only the importance of quantitative plaque burden, but also its composition in determining ACS risk. Dr van den Hoogen expands our knowledge to add a potential timeline of ACS from these data. A higher plaque burden, and especially a significant low attenuation plaque burden, should be a call to action by informing the urgency as well as the aggressiveness of treatment.

The current findings should also be taken into context as this study is encouraging, but not the last word. The ICONIC patients were derived from the retrospective CONFIRM registry covering the years 2003 to 2009. This was not a randomized trial and the bias that is inherent in observational registries needs to be acknowledged. In addition, patients in the 2000s era were treated less aggressively with more lenient lipid and blood pressure goals, which could affect plaque composition as well as the likelihood, type, and timing of ACS.⁷ Patients in the ICONIC study were also scanned using older generation 64 slice CT scanners where the lower temporal and spatial resolution and older motion correction and reconstruction techniques can lead to higher plaque measurement variability. This could explain, in part, heterogeneity of associations for cross sectional atherosclerotic burden and high-risk plaque measures between and within lesion measures as well as plaque volume measures between patients those with either early or late ACS and those without ACS. The statistical power of the 129 total patients with ACS and the identified single culprit lesion could be inadequate to make up for the high variability and inter-quartile ranges of plaque measurements. Importantly, we should also acknowledge that the number of events within the four referenced CCTA plaque studies are similarly limited with only 293 total ACS events in the literature, highlighting the need for additional contemporary data to refine and confirm these associations. However, the consistency of the contemporary CCTA plaque studies reviewed above and the current study suggest that differences in plaque measurements and treatments in different eras may not be a significant concern.

How does the current data inform the future of plaque analysis and risk stratification? The recently published CAD RADS 2.0 paper is the first guideline to suggest including an ordinal scale of plaque measurement into routine CCTA assessments.¹⁰ The CAD RADS 2.0 authors believe that improvements in CCTA technology and plaque characterization, especially with companies developing high accuracy machine learning algorithms, will enhance multidimensional plaque measurements to bring these data into the mainstream. These quantitative plaque data have the potential to reshape our risk stratification and individualize decisions for more (or less) aggressive treatments. Data such as those from the current paper by van de Hoogen and colleagues suggest that plaque components may also stratify patients into higher risk ‘temporally vulnerable’ patients for early ACS. To inform these data further, additional investigations could also be considered such as further investigating volumetric thresholds (large vs. smaller necrotic cores), coronary vessel locations (e.g. branch points, proximal vessels), and other risk enhancers, such as pericoronary fat. Investigations into whether repeat plaque assessment after initiation of appropriate treatments can refine risk are also needed. Looking to the future, the field clearly needs to pursue large randomized control trials to test whether coronary plaque components truly define a higher risk that can be mitigated with lifestyle or pharmacologic interventions. Fortunately, the field has never been better prepared to investigate the intersection of three dimensional CCTA plaque measures and clinical risk to not only identify the vulnerable plaque and the vulnerable patient, but to infer the fourth dimension, a potential timeline to ACS.

Funding

Research grants from the NIH, Population Health Research Institute, Bayer, Sanofi, Eli Lilly, Kestra, Medic One Foundation.

Data Availability

No new data were generated or analysed in support of this research.

References

Author notes