Comparative differences in the atherosclerotic disease burden between the epicardial coronary arteries: quantitative plaque analysis on coronary computed tomography angiography

Abstract

Aims

Anatomic series commonly report the extent and severity of coronary artery disease (CAD), regardless of location. The aim of this study was to evaluate differences in atherosclerotic plaque burden and composition across the major epicardial coronary arteries.

Methods and results

A total of 1271 patients (age 60 ± 9 years; 57% men) with suspected CAD prospectively underwent coronary computed tomography angiography (CCTA). Atherosclerotic plaque volume was quantified with categorization by composition (necrotic core, fibrofatty, fibrous, and calcified) based on Hounsfield Unit density. Per-vessel measures were compared using generalized estimating equation models. On CCTA, total plaque volume was lowest in the LCx (10.0 ± 29.4 mm³), followed by the RCA (32.8 ± 82.7 mm³; P < 0.001), and LAD (58.6 ± 83.3 mm³; P < 0.001), even when correcting for vessel length or volume. The prevalence of ≥2 high-risk plaque features, such as positive remodelling or spotty calcification, occurred less in the LCx (3.8%) when compared with the LAD (21.4%) or RCA (10.9%, P < 0.001). In the LCx, the most stenotic lesion was categorized as largely calcified more often than in the RCA and LAD (55.3% vs. 39.4% vs. 32.7%; P < 0.001). Median diameter stenosis was also lowest in the LCx (16.2%) and highest in the LAD (21.3%; P < 0.001) and located more distal along the LCx when compared with the RCA and LAD (P < 0.001).

Conclusion

Atherosclerotic plaque, irrespective of vessel volume, varied across the epicardial coronary arteries; with a significantly lower burden and different compositions in the LCx when compared with the LAD and RCA. These volumetric and compositional findings support a diverse milieu for atherosclerotic plaque development and may contribute to a varied acute coronary risk between the major epicardial coronary arteries.

coronary computed tomography angiography, coronary artery disease, coronary artery plaque composition

Introduction

Atherosclerotic plaque imaging has rapidly advanced from initial studies using invasive techniques, such as intra-vascular ultrasound or optical coherence tomography^1,2 to more recent advancements using coronary computed tomography angiography (CCTA) as a non-invasive alternative for qualitative and quantitative measurement of atherosclerosis.^3–5 Within the field of anatomic imaging, there has been extensive research establishing the prognostic significance and therapeutic benefit from intervention based on the severity and location of obstructive coronary artery disease (CAD).^6–9 Specifically, prior invasive angiographic data revealed that the left circumflex (LCx) coronary artery is more often observed with single when compared with multivessel CAD when compared with that in the left anterior descending (LAD) or right coronary artery (RCA).¹⁰ Moreover, among patients with STEMI, the location of a culprit lesion is reported less often in the LCx when compared with the LAD or RCA.¹¹ In stable patients, lower coronary artery calcium scores were also reported in the LCx when compared with the LAD or RCA.¹² These findings in largely smaller cohorts suggest a varied milieu for atherosclerosis development. To date, comprehensive comparisons between the epicardial coronary arteries concerning the presence and severity of coronary atherosclerosis have not been reported.

The Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography (PARADIGM) registry previously reported on alterations in atherosclerotic plaque with statin therapy.¹³ In the current report, we undertook a comparative analysis of differences in the burden and composition of quantitative atherosclerotic plaque by the location of the epicardial coronary artery; primarily comparing the LCx with LAD and RCA. Differences were also compared based on correction for vessel volume, including analysis by the percent atheroma volume (PAV).

Methods

Study design

PARADIGM was a multinational, dynamic observational cohort that prospectively enrolled patients undergoing CCTA between 2003 and 2015.¹⁴ The research protocol was approved by each centre’s institutional review board. Details of the PARADIGM registry are found in the report by Lee et al.¹⁵

Patient enrolment

A total of 2252 patients with suspected CAD undergoing CCTA were prospectively enrolled from 13 sites in 7 countries (Brazil, Canada, Germany, Italy, Portugal, South Korea, and the USA).¹⁴ For this analysis, patients that had undergone revascularization (defined as percutaneous coronary intervention and/or coronary artery bypass grafting; n = 736) were excluded, as well as patients with missing analysis of ≥1 coronary artery on CCTA (n = 245). Thus, the current analysis included 1271 patients (n = 3813 vessels).

CCTA acquisition and interpretation

All CCTAs were performed in accordance with the Society of Cardiovascular Computed Tomography guidelines.^16,17 Datasets from each participating site were transferred to a core laboratory for blinded image analysis. Coronary atherosclerosis was evaluated on multiplanar and cross-sectional CCTA images. All computations were performed by level III experienced readers masked to clinical data, using quantitative plaque software (QAngioCT Research Edition v2.1.9.1, Medis Medical Imaging Systems, Leiden, the Netherlands).¹⁸

All coronary arteries with a diameter ≥2 mm were evaluated, according to the 17-segment American Heart Association model for coronary segment classification.¹⁷ Presence of plaque was defined as any tissue ≥1 mm² identified in >2 planes, within or adjacent to the lumen that could be discriminated from surrounding pericardial tissue, epicardial fat, or lumen.^17,19 Quantitative analysis was performed on a per-segment level. To generate vessel length (mm), vessel volume (mm³), lumen volume (mm³), and per-vessel plaque volume (mm³), measurements of all segments of each vessel, including side branches, were summed. PAV was calculated as follows: [(PV/vessel volume) × 100] %. Based on established Hounsfield Unit (HU) ranges, plaque composition was categorized as calcified (>350 HU)²⁰, fibrous (131–350 HU), and low-density [necrotic core (≤30 HU) and fibrofatty (31–130 HU)]^13,20,21 The proportion of total PV of the compositional subtypes was calculated as: subtype % = [(subtype PV/total per−vessel PV) × 100] %.

Furthermore, individual lesions were evaluated for composition (visually classified as calcified, mixed, or non-calcified), diameter stenosis (%), and high-risk plaque (HRP) defined as ≥2 of the following features: low-attenuation plaque, spotty calcification, positive remodelling, or napkin ring sign^19,22 and distance from the ostium to the point of minimal lumen diameter (mm). Low-attenuation plaque was defined as any lesion containing ≥1 voxel(s) with HU ≤30.^19,23 Spotty calcification was defined by the presence of intra-lesional calcification <3 mm.^22,24 A remodelling index was calculated as a maximal lesion vessel area divided by proximal reference vessel area, with positive remodelling defined by a remodelling index ≥1.1.²⁵ A napkin ring sign was defined cross-sectionally with a central area of low attenuation plaque and a surrounding ring with higher attenuation plaque.

Study endpoints

All analyses were performed on a per-vessel basis. The primary aim of this report was to compare differences in CCTA-derived atherosclerotic plaque volume between the three major epicardial coronary arteries. Secondary endpoints included comparisons by atherosclerotic plaque compositional subgroups and the location of the most stenotic lesion in the coronary artery.

Statistical analysis

Continuous variables are presented as mean ± SD or median with interquartile range (IQR), while categorical variables are presented as absolute numbers and percentages. Differences between categorical variables were compared using a χ² or Fisher’s exact test. Continuous variables were compared using either a paired test (Friedman test for three-way or a Wilcoxon signed-rank test) or unpaired test (Mann–Whitney U test for per-lesion comparison), as appropriate. To account for within patient clustering of data, generalized estimating equations (GEE) models were used, including linear and logistic models. Odds ratios (ORs) and 95% confidence intervals were calculated. When noted, the GEE models included the atherosclerotic cardiovascular disease risk score, as a covariate. Two-tailed P-values <0.05 were considered statistically significant. All analyses were performed in SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) and SPSS Statistics version 25 (IBM Corporation, Armonk, NY, USA).

Results

Baseline characteristics

From 2252 patients enrolled in the PARADIGM registry, 1271 (mean age 60.3 ± 9.3 years; 57% men) were included in the current analysis (Table 1). A majority of enrolled patients were symptomatic prior to their CCTA (81%). The overall prevalence of CAD risk factors was 51.8% for hypertension, 37.5% for hyperlipidaemia, 19.8% for diabetes mellitus, and 18.4% for smoking.

Table 1

Baseline clinical characteristics of the 1271 enrolled patients

	Descriptive statistics (N = 1271)
Age, mean ± SD (years)	60.3 ± 9.3
Male sex (%)	724 (57.0)
BMI, mean ± SD (kg/m2)	25.3 ± 3.3
ASCVD risk score, median (IQR) (%)	9.3 (4.4-17.6)
Chest pain history (%)
Asymptomatica	182 (14.3)
Non-cardiac chest pain	115 (9.1)
Atypical chest pain	907 (71.8)
Typical angina	48 (3.8)
CAD risk factors (%)
Diabetes mellitus	251 (19.8)
Hypertension	655 (51.8)
Hyperlipidaemia	474 (37.5)
Family history of CAD	363 (28.6)
Current smoker	232 (18.4)
Medications (%)
Aspirin	452 (36.2)
β-Blockers	332 (26.6)
Calcium channel blockers	261 (21.0)
Diuretics	111 (8.9)
RAAS inhibitors	350 (28.1)
Statins	474 (38.9)

a

Asymptomatics in this registry met clinical indications for CCTA and often were referred for pre-operative risk evaluation, prior stress testing, or had a history of non-cardiac atherosclerosis.

ASCVD risk score, atherosclerotic cardiovascular disease risk score; BMI, body mass index; CAD, coronary artery disease; RAAS inhibitors, renin–angiotensin–aldosterone system inhibitors.

Quantitative measurement of atherosclerotic plaque on CCTA

CCTA measurements of the three major coronary arteries are presented in Table 2. On average, the LAD was the longest vessel (169.0 ± 57.8 mm), whereas the RCA was the largest vessel in terms of volume (1042.5 ± 604.0 mm³). The LCx was smaller in terms of vessel length (98.5 ± 43.8 mm) and vessel volume (476 ± 305.9 mm³) than the LAD and RCA (P < 0.001 for both). Total plaque volume was smallest in the LCx (10.0 ± 29.4 mm³), followed by the RCA (32.8 ± 82.7 mm³; P < 0.001), and LAD (58.6 ± 83.3 mm³; P < 0.001). After correcting for vessel volume, the LCx remained the vessel with the smallest percent atheroma volume (PAV 2.0 ± 5.2%), compared with the LAD (6.4 ± 8.1%; P < 0.001) and the RCA (2.8 ± 6.3%; P < 0.001). For all compositional subtypes, the LAD contained the highest plaque volume, followed by the RCA and lastly the LCx. Furthermore, the number of lesions differed significantly among the coronary arteries, with the LCx containing fewer lesions (0.42 ± 0.77 per artery; P < 0.001) and fewer HRP lesions (0.04 ± 0.20 per artery; P < 0.001). The prevalence of ≥2 HRP features was significantly lower in the LCx (3.8%) when compared with the LAD (21.4%) and RCA (10.9%, P < 0.001). The same was noted for the individual HRP features, such as spotty calcification (P < 0.001) or positive remodelling (P < 0.001).

Table 2

Comparison of atherosclerotic plaque volume and composition between the major epicardial coronary arteries

	Mean ± SD or %			P-value
Vessel analysis	LAD (N = 1271)	RCA (N = 1271)	LCx (N = 1271)	Overalla	LCx vs. LADb	LCx vs. RCAb
Vessel length (mm)	169.0 ± 57.8	154.1 ± 51.5	98.5 ± 43.8	<0.001	<0.001	<0.001
Vessel volume (mm3)	900.4 ± 401.2	1042.5 ± 604.0	476.3 ± 305.9	<0.001	<0.001	<0.001
Lumen volume (mm3)	841.7 ± 381.6	1009.8 ± 586.8	466.3 ± 301.3	<0.001	<0.001	<0.001
Plaque volume (mm3)	58.6 ± 83.3	32.8 ± 82.7	10.0 ± 29.4	<0.001	<0.001	<0.001
Necrotic core (≤30 HU)	1.6 ± 5.3	0.6 ± 3.3	0.1 ± 1.2	<0.001	<0.001	<0.001
Fibrofatty (31–130 HU)	12.0 ± 24.2	5.8 ± 18.3	1.1 ± 5.2	<0.001	<0.001	<0.001
Fibrous (131–350 HU)	25.3 ± 36.8	15.8 ± 40.9	4.7 ± 14.6	<0.001	<0.001	<0.001
Calcified (>350 HU)	19.7 ± 41.2	10.7 ± 37.4	4.1 ± 14.4	<0.001	<0.001	<0.001
PAV (%)	6.4 ± 8.1	2.8 ± 6.3	2.0 ± 5.2	<0.001	<0.001	<0.001
Number of lesions per vessel	1.10 ± 0.99	0.72 ± 1.15	0.42 ± 0.77	<0.001	<0.001	<0.001
≥2 HRP features (%)	21.3	10.9	3.8	<0.001
Low-attenuation plaque (%)	15.1	7.2	1.8	<0.001
Spotty calcification (%)	13.8	6.3	2.9	<0.001
Positive remodelling (%)	56.1	33.0	22.7	<0.001
Napkin-ring sign (%)	0.5	0.2	0.0	0.002
Number of HRP lesions per vessel	0.21 ± 0.43	0.11 ± 0.37	0.04 ± 0.20	<0.001	<0.001	<0.001

HRP, high-risk plaque; HU, Hounsfield Units; LAD, left anterior descending; LCx, left circumflex; PAV, percent atheroma volume; RCA, right coronary artery.

^aFriedman test.

^bWilcoxon signed-rank test.

Atherosclerotic plaque composition on CCTA

The prevalence of plaque across the different coronary arteries is presented in Figure 1A. The prevalence of any plaque was the lowest in the LCx (29.8%), followed by the RCA (39.8%; P < 0.001) and LAD (69.8%; P < 0.001). Similarly, the presence of low-density plaque (combining necrotic core and fibrofatty plaque) was lowest in the LCx, followed by RCA and LAD (20.9%, 34.2%, and 64.4%, respectively, P < 0.001).

Figure 1

Overview of plaque composition findings per-vessel. (A) The prevalence of low-density (necrotic core and fibrofatty) plaque across the coronary arteries is presented in pie charts. Low-density plaque was less prevalent in the LCx (P < 0.001). (B) Mean proportions of total plaque volume made up by compositional subtypes are presented in bar charts. In the LCx, necrotic core (≤30 HU) and fibrofatty plaque (31–130 HU) comprised less of the total plaque volume, whereas calcified plaque (>350 HU) made up larger proportions, when compared with the LAD and RCA.

Moreover, both necrotic core (LCx 0.7%; RCA 1.7%; LAD 2.3%, P < 0.001) and fibrofatty plaque (LCx 10.3%; RCA 16.6%; LAD 18.9%, P < 0.001) comprised the smallest proportion of the total plaque volume in the LCx (Figure 1B). The mean proportion of calcified plaque was highest in the LCx (39.4%) when compared with the RCA (31.3%) and LAD (31.2%) (P < 0.001), whereas proportions of fibrous plaque were similar in all three vessels.

Comparisons of atherosclerotic plaque using regression modelling

To consider the within patient clustering of vessels, we compared plaque compositional subtypes using a GEE logit model (Table 3). The multivariate model included the atherosclerotic cardiovascular disease risk score and vessel length as covariates. The adjusted odds of any plaque classified as necrotic core was 3.5- and 2.8-fold higher in the LAD (P < 0.001) and RCA (P < 0.001) vs. the LCx. Fibrofatty plaque was also significantly more likely to be present in the LAD (OR 4.1; P < 0.001) and RCA (OR 2.3; P < 0.001) than in the LCx; while the presence of any fibrous or calcified plaque was similar across the coronary arteries.

Table 3

Comparison of the odds of atherosclerotic disease prevalence and the ratio of plaque composition subgroups in the LAD and RCA vs. the LCx

	Adjusted odds ratio (aOR) and 95% confidence interval (CI)
	LAD vs. LCx		RCA vs. LCx
	aOR of any plaque (95% CI)a	P-value	aOR of any plaque (95% CI)a	P-value
Necrotic core	3.5 (2.6–4.6)	<0.001	2.8 (2.0–3.9)	<0.001
Fibrofatty	4.1 (2.8–6.0)	<0.001	2.3 (1.6–3.3)	<0.001
Calcified	1.2 (0.8–1.9)	0.379	0.8 (0.5–1.2)	0.280
	Ratio of composition type volume/total per-vessel plaque volume
	LAD vs. LCx		RCA vs. LCx
	Ratio (95% CI)b	P-value	Ratio (95% CI)b	P-value
Necrotic core	1.8 (1.3–2.6)	0.001	1.7 (1.2–2.4)	0.004
Fibrofatty	1.8 (1.5–2.2)	<0.001	1.6 (1.2–2.0)	<0.001
Calcified	0.8 (0.7–0.9)	<0.001	0.8 (0.6–0.9)	<0.001

LAD, left anterior descending; LCx, left circumflex; RCA, right coronary artery.

a

The logit GEE model calculated the aOR controlling for vessel length, atherosclerotic cardiovascular disease risk score, and statin use as covariates.

b

Calculated from a linear GEE-model, adjusted for atherosclerotic cardiovascular disease risk score, and statin use. Ratios were calculated by dividing the proportions of compositional subtypes, in two vessels. E.g. the ratio for necrotic core in the LAD vs. LCx = ([necrotic core volume/plaque volume] _LAD / [necrotic core volume/plaque volume] _LCx).

In a GEE linear model, the ratio of necrotic core to total vessel plaque volume was nearly two-fold higher in the LAD (ratio: 1.8; P = 0.001) and RCA (ratio: 1.7; P = 0.004) than in the LCx. Similar observations were made for the ratio of fibrofatty plaque (ratio LAD vs. LCx: 1.8; ratio RCA vs. LCx: 1.6; P < 0.001 for both). However, the ratio of calcified plaque to total vessel plaque volume was significantly lower in the LAD (ratio 0.8; P < 0.001) and RCA (ratio 0.8; P < 0.001) than in the LCx; all comparisons were adjusted for the atherosclerotic cardiovascular disease risk score and statin use. Proportions of fibrous plaque did not differ significantly between the coronary arteries.

Comparisons of CCTA characteristics in the most stenotic lesion

In the LCx, the most stenotic lesion was categorized as largely calcified more so than in the RCA and LAD (55.8% vs. 39.4% vs. 32.7%, respectively; P < 0.001; see Figure 2A). Diameter stenosis was also lowest in the LCx [16.2% (IQR 9.4–25.1%)], followed by the RCA [19.3% (IQR 10.5–28.4%); P = 0.017], and the LAD [21.3% (IQR 12.5–31.4%); P < 0.001; see Figure 2B]. Distance from the ostium to the most severe stenosis was similar in the LCx and RCA [33.6 mm (IQR 22.4–47.3 mm) vs. 33.8 mm (IQR 21.1–64.2 mm); P = 0.260] and was shorter in the LAD [28.5 mm (IQR 18.0–38.6 mm); P < 0.001]. As such, the most stenotic lesion was more often located more distal in the LCx, occurring at 34.4% of the length of the vessel (as measured from the ostium), when compared with 21.8% for the RCA (P < 0.001) and 17.0% for the LAD (P < 0.001).

Figure 2

Characteristics of the worst stenosis across the coronary arteries. (A) Composition of the most stenotic lesion in the coronary artery, based on visual analysis, is presented in pie charts. Most stenotic lesions were classified as calcified more often in the LCx when compared with the LAD or RCA. (B) Left to right: diameter stenosis (%), distance from the aortic ostium to point of minimal lumen diameter (mm), and location within the coronary vessel (% of length from the ostium). Lesions were less stenotic and located more distal in the LCx compared with the other coronary arteries. Bars represent medians with IQR and were compared using the Mann–Whitney U test. *P < 0.001; **P < 0.05.

Discussion

While there is abundant evidence regarding the prevalence and risk associated with various stenosis and plaque findings on CCTA, there has been little attention to differences in the burden and composition of atherosclerotic plaque between the major epicardial coronary arteries. Our results revealed that the LCx contained a lower burden of plaque, even when correcting for vessel volume (P < 0.001). Compared with the other coronary arteries, the LCx also showed a different compositional structure of plaque, containing a larger proportion of calcified plaque along with smaller proportions of low-density plaque. Moreover, low-density plaque, which is often associated with higher risk for future coronary events, was less often present in the LCx when compared with the LAD and RCA. These findings have implications for disease detection and support the variable findings reported for ischaemia provocation across the epicardial coronary tree. Importantly, the occurrence of more distal disease that is more calcified with a lower plaque burden and fewer high-risk plaque features is congruent with more stable atherosclerosis and a reduced likelihood for future ischaemic events.

Jeopardized myocardium and risk across the epicardial coronary arteries

Risk assessment of patients based on angiographic findings have been previously reported. Several risk scores, such as the Duke CAD prognostic index⁶ or SYNTAX score,²⁶ uniquely identify risk associated with an LAD stenosis, especially in a proximal location. This higher risk status relates to the sizeable proportion of jeopardized myocardium subtended by the LAD.²⁷ Additionally, the prevalence of culprit lesions when examined in STEMI series is notably less in the LCx. Additional research findings also reveal that lateral electrocardiographic leads or LCx stress imaging vascular territory abnormalities have a significantly lower diagnostic accuracy; albeit also impacted upon by suboptimal localization and visualization.

The evidence is far from robust and for most of the analyses ranking disease burden and risk, the LCx has historically been the focus of fewer and smaller patient series. Several studies including patients with suspected CAD have shown a lower prevalence of significant stenosis in the LCx.^28,29 The absence of coronary stenosis occurs more often in the LCx (44%) when compared with the LAD (14%); in addition, a more severe stenosis (≥50%) is more often observed in the LAD when compared with the RCA and LCx.²⁸ In addition, Kang et al.²⁹ examined patients with significant stenosis on invasive coronary angiography, revealing the lowest prevalence of obstructive CAD in the LCx. These data support the improved survival reported for patients with one-vessel obstructive CAD in the LCx when compared with that of patients with isolated obstructive CAD in the LAD or RCA.³⁰

Potential mechanisms influencing atherosclerotic plaque between the epicardial coronary arteries

Our analysis reveals a lower burden of atherosclerosis in the LCx on CCTA, suggesting the possibility of a more stable and less turbulent atherosclerotic milieu in that vessel. These data are supported by prior evidence noting higher fractional flow reserve measures in the LCx when compared with the LAD, despite equivalent percent stenosis.³¹ It is purported that local haemodynamic forces play an important role in the development of atherosclerosis in the coronary arteries.^32,33 Wall shear stress, the drag force of circulating blood onto the endothelial surface of the artery, is not uniformly distributed across the coronary arteries, with areas of low wall shear stress located at the main bifurcation of the left coronary artery and its proximal segments,^34–36 especially when the bifurcation angle is more obtuse.³⁷ The strong correlation between low wall shear stress and atherogenesis has been confirmed,^38–40 potentially explaining our observed differences in atherosclerotic burden between the different coronary arteries.

Additionally, Wasilewski et al.⁴¹ hypothesized that the squeezing of the septal perforators of the LAD during systole could result in retrograde flow in the LAD segment proximal to the septal perforators, leading to disrupted flow and consequently to the formation of atherosclerosis. Although these studies are not definitive, they mirror our observed findings of a lower burden and severity of coronary atherosclerosis in the LCx when compared with the LAD and RCA.

Study limitations

The current study has several limitations. The design was that of an observational registry, which lends itself to selection and other biases. Furthermore, plaque quantification software used herein is semi-automated, requires tracing of centrelines in the coronary arteries, and is time consuming. Side branches, especially the obtuse marginal side branches of the LCx, were often tortuous and therefore more complex to trace by hand to their full length. This may lead to variable measurement issues across the coronary arteries.

Conclusions

Our findings revealed that atherosclerotic burden differs among the coronary arteries, with the LCx being the vessel with the lowest plaque burden. Moreover, varied admixtures were noted with more calcified plaque in the LCx when compared with the LAD and RCA, potentially suggesting more stabilized CAD. In addition, low-density plaque (necrotic core and fibrofatty plaque) was more prevalent in the LAD and RCA (when compared with the LCx). This research provides further insight into the possible explanation for the uneven distribution of observed culprit lesions among the coronary arteries and the varied prognosis reported in the literature.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Acknowledgements

The authors acknowledge the PARADIGM investigators for their continued collaboration.

Data availability

The data underlying this article cannot be shared publicly due to the patients' privacy. Data may be available upon reasonable request to the corresponding author, pending investigator approval of the study hypothesis and presence of an institutional data use agreement.

Funding

This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation funded by the Ministry of Science and Information and Communications Technology of Korea (Grant no. 2012027176). Additional funding was provided by a gift from the Dalio Foundation (New York, NY) and the Michael Wolk Foundation (New York, NY).

Conflict of interest: K.C. is a non-compensated medical advisory board member of Heartflow Inc. J.K.M. has equity interest and is an employee of Cleerly, Inc. H.S. serves on the scientific advisory board of Phillips, has equity interest in Covanos, Inc., and has research grants from Medtronic, Abbott Vascular, and Phillips. L.J.S. serves on the scientific advisory board for Covanos, Inc. All other authors report no conflict of interest.

Author notes

Hyuk-Jae Chang and Leslee J Shaw authors serve as co-senior authors of this manuscript.

A full list of PARADIGM investigators is provided in the Supplementary dataonline, Appendix.