Abstract
Background
Half of women with ischemic symptoms have non-obstructive coronary artery disease (CAD), while the pathophysiology of their condition has not been characterized. Noncalcified (NCP) and low-attenuation plaque (CT density<30 Hounsfield units, LAP) burden quantified from coronary computed tomography angiography (CCTA) is associated with ischemia in patients with obstructive CAD. We hypothesize that NCP burden is related to angina in women with ischemic symptoms and Non-Obstructive Coronary Arteries (INOCA).
Methods
Women with INOCA enrolled in the WARRIOR trial were evaluated for angina severity with Seattle Angina Questionnaire (SAQ) at study entry. Baseline CCTA of 117 women were quantitatively analyzed with AI-based software for NCP, LAP and calcified plaque (CP) volumes and burdens (%, normalized to vessel volume) across the coronary tree. Machine-learning ischemia risk score (ML-IRS) integrating quantitative lumen and plaque features from CCTA was automatically measured.
Results
Among 109 women with visible plaque on CCTA (age 61.9, SD 10.3 years) median total plaque burden is 26.6% (IQR 18.6,32.0) and median SAQ score is 61.4 (IQR 54.6,69.1). Patients with more severe angina (SAQ ≤ 60) are younger (58.1 vs 62.0 years, p = 0.015), have higher total cholesterol (195 vs 165 mg/dL, p = 0.006), but less frequently receive statins (31.8 vs 64.4%, p = 0.006) compared with patients with SAQ > 60. Patients with SAQ ≤ 60 have higher total plaque (33.3 vs 24.3%, p = 0.001), and NCP burden (33.3 vs. 23.2%, p = 0.00065), and lower CP burden (0.0 vs. 0.3%, p = 0.005) compared with patients with SAQ > 60. On multivariable linear regression adjusted for risk factors, higher NCP burden (β = −0.50, p = 0.001), LAP burden (β = −4.50, p = 0.008) and ML-IRS (β = −3.09, p = 0.04) are associated with lower SAQ score, i.e. more severe angina.
Conclusions
In women with INOCA, high-risk atherosclerotic plaque phenotypes are related to more severe angina.
Plain language summary
Severe narrowings of coronary arteries (i.e. the blood vessels that supply oxygenated blood to the heart), are the typical cause of chest pain in patients with atherosclerotic coronary artery disease. This type of chest pain is called angina. However, especially in women, angina can occur even if no major narrowings of coronary arteries are found using scans of the heart. We used artificial intelligence-assisted non-invasive imaging of coronary arteries to find out what aspects of this non-obstructive coronary atherosclerosis is associated with symptom severity in women without obvious artery narrowing. We observed that coronary plaques, which are buildups of fats and other substances in the artery walls, have a different composition in women with more severe angina. This information expands our understanding of why angina occurs in such patients and provides a rationale for possibly treating these women using anti-atherosclerotic drugs in the future.
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Acknowledgements
This study was primarily supported by grants from the NHLBI R01HL151266 and 1R01HL148787. It was also supported by CDMRP-DoD W81XWH-17-2-0030 and McJunkin Family Foundation through funds distributed by the University of Florida, Department of Medicine, Clinical Research Consortium CDRN-1501-26692, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, CA, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, the Linda Joy Pollin Women’s Heart Health Program, the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, CA; and the VA Women’s Health Practice-Based Research Network VA HSR&D SDR 10-012. R.W. is supported by a Polish National Science Center (grant number 2021/43/D/NZ5/02434) and Medical Research Agency (grant number KPOD.07.07-IW.07-0150/24). R.P. was supported by a grant from the Miriam and Sheldon G Adelson Medical Research Foundation.
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Drs Berman, Slomka, and Dey have received software royalties from Cedars-Sinai Medical Center and report equity in APQ Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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Wolny, R., Flores Tomasino, G., Grodecki, K. et al. Artificial intelligence-enabled plaque characterization from coronary computed tomography establishes basis of angina in women with nonobstructive atherosclerosis. Commun Med (2026). https://doi.org/10.1038/s43856-026-01668-6
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DOI: https://doi.org/10.1038/s43856-026-01668-6
