Observational Study

. 2025 Jun;18(6):e018235.

doi: 10.1161/CIRCIMAGING.125.018235. Epub 2025 Mar 31.

AI-Quantitative CT Coronary Plaque Features Associate With a Higher Relative Risk in Women: CONFIRM2 Registry

Gudrun M Feuchtner¹, Pietro G Lacaita¹, Jeroen J Bax², Fatima Rodriguez³, Rine Nakanishi⁴, Gianluca Pontone^{5

6}, Saima Mushtaq⁷, Ronny R Buechel⁸, Christoph Gräni⁹, Amit R Patel¹⁰, Cristiane C Singulane¹⁰, Andrew D Choi¹¹, Mouaz Al-Mallah¹², Daniele Andreini¹³, Ronald P Karlsberg¹⁴, Geoffrey Cho¹⁴, Carlos E Rochitte¹⁵, Mirvat Alasnag¹⁶, Ashraf Hamdan¹⁷, Filippo Cademartiri¹⁸, Erica Maffei¹⁹, Hugo Marques²⁰, Pedro M Gonçalves Pereira²⁰, Himanshu Gupta²¹, Martin Hadamitzky²², Omar Khalique²³, Dinesh Kalra²⁴, James D Mills²⁵, Nick S Nurmohamed²⁶, Paul Knaapen²⁷, Matthew Budoff²⁸, Kashif Shaikh²⁹, Enrico Martin³⁰, David M German³¹, Maros Ferencik³¹, Andrew C Oehler³², Roderick Deaño³³, Prashant Nagpal³⁴, Marly Van Assen³⁵, Carlo Nicola De Cecco³⁵, Borek Foldyna³⁶, Jan Michael Brendel³⁶, Victor Y Cheng³⁷, Kelley Branch³⁸, Marcio Bittencourt³⁹, Sabha Bhatti⁴⁰, Venkateshwar Polsani⁴¹, George Wesbey⁴², Rhanderson Cardoso⁴³, Ron Blankstein⁴³, Augustin Delago^{44

45}, Amit Pursnani^{46

47}, Amro Alsaid⁴⁸, Stephen Bloom⁴⁹, Vasileios Kamperidis⁵⁰, Fabian Barbieri⁵¹, Melissa Aquino⁵², Ibrahim Danad⁵³, Alexander van Rosendael²

Affiliations

¹ Department of Radiology, Medical University of Innsbruck, Austria (G.M.F., P.G.L.).
² Department of Cardiology, Leiden University Medical Center, the Netherlands (J.J.B., A.R.).
³ Division of Cardiovascular Medicine, Stanford University School of Medicine, Paolo Alto, CA (F.R.).
⁴ Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan (R.N.).
⁵ Department of Perioperative Cardiology and Cardiovascular Imaging, Centro Cardiologico Monzino Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy (G.P.).
⁶ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy (G.P.).
⁷ Perioperative Cardiology and Cardiovascular Imaging Department, Centro Cardiologico Monzino IRCCS, Milan, Italy (S.M.).
⁸ Department of Nuclear Medicine, Cardiac Imaging, University Hospital and University of Zurich, Switzerland (R.R.B.).
⁹ Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (C.G.).
¹⁰ Division of Cardiovascular Medicine, University of Virginia, Charlottesville (A.R.P., C.C.S.).
¹¹ Department of Cardiology and Radiology, George Washington University, Washington, DC (A.D.C., ).
¹² Department of Cardiology, Houston Methodist, TX (M.A.-M.,.).
¹³ Division of University Cardiology, IRCCS Galeazzi Sant'Ambrogio, Department of Biomedical and Clinical Sciences, University of Milan, Italy (D.A.).
¹⁴ Cardiovascular Research Foundation of Southern California, Cedars-Sinai Heart, David Geffen School of Medicine, University of California Los Angeles (R.P.K., G.C.).
¹⁵ Heart Institute, InCor, University of São Paulo Medical School, Brazil (C.E.R.).
¹⁶ Cardiac Center, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia (M. Alasnag).
¹⁷ Department of Cardiology, Rabin Medical Center, Petah Tikva and Tel Aviv University, Israel (A.H.).
¹⁸ IRCCS SYNLAB SDN, Naples, Italy (F.C.).
¹⁹ Department of Radiology, Istituto di Ricovero e Cura a Carattere (IRCCS) SYNLAB SDN, Naples, Italy (E. Maffei).
²⁰ UNICA, Unit of Cardiovascular Imaging, Hospital da Luz, Lisboa, Portugal (H.M., P.M.G.F).
²¹ Cardiac Imaging, Heart and Vascular Institute, Valley Health System, Paramus, NJ (H.G.).
²² Department of Radiology and Nuclear Medicine, German Heart Center Munich, Germany (M.H.).
²³ Division of Cardiovascular Imaging, St. Francis Hospital and Heart Center, Roslyn, NY (O.K.).
²⁴ Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, KY (D.K.).
²⁵ Department of Cardiology, West Virginia University Heart and Vascular Institute, Morgantown (J.D.M.).
²⁶ Department of Cardiology and Department of Vascular Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands (N.S.N.).
²⁷ Department of Cardiology, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands (P.K.).
²⁸ The Lundquist Institute, Torrance, CA (M. Budoff).
²⁹ University of Tennessee Medical Center, Knoxville (K.S.).
³⁰ Division of Cardiology, MercyOne-Iowa Heart Center, Des Moines, IA (E. Martin).
³¹ Knight Cardiovascular Institute, Oregon Health & Science University, Portland (D.M.G., M.F.).
³² Allegheny Health Network Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA (A.C.O.).
³³ Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison (R.D.).
³⁴ Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison (P.N.).
³⁵ Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA (M.V.A., C.N.D.C.).
³⁶ Department of Radiology, Cardiovascular Imaging and Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (B.F., J.M.B.).
³⁷ Minneapolis Heart Institute, MN (V.Y.C.).
³⁸ Division of Cardiology, Cardiovascular Clinical Trials, University of Washington, Seattle (K.B.).
³⁹ Heart and Vascular Institute, University of Pittsburgh Medical Center, PA (M. Bittencourt).
⁴⁰ National Institute of Cardiovascular Diseases, Karachi, Pakistan (S. Bhatti).
⁴¹ Piedmont Heart Institute, Atlanta, GA (V.P.).
⁴² Department of Cardiovascular Computed Tomography, Scripps Clinic, La Jolla, CA (G.W.).
⁴³ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (R.C., R.B.).
⁴⁴ Medical Data Research Collaborative, United Kingdom (A.D.).
⁴⁵ Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA (A.D.).
⁴⁶ Cardiology, Endeavor NorthShore Cardiovascular Institute, Evanston, IL (A.P.).
⁴⁷ Pritzker School of Medicine, University of Chicago, IL (A.P.).
⁴⁸ Department of Cardiac Imaging, Baylor Scott & White The Heart Hospital Plano, TX (A.A.).
⁴⁹ Midwest Heart and Vascular Associates, Kansas City, MO (S. Bloom).
⁵⁰ 1st Cardiology Department, Medical School, Aristotle University of Thessaloniki, Greece (V.K.).
⁵¹ Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany (F.B.).
⁵² Cleerly Health, Denver, CO (M. Aquino).
⁵³ Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands (I.D.).

PMID: 40162910
PMCID: PMC12173162
DOI: 10.1161/CIRCIMAGING.125.018235

Observational Study

AI-Quantitative CT Coronary Plaque Features Associate With a Higher Relative Risk in Women: CONFIRM2 Registry

Gudrun M Feuchtner et al. Circ Cardiovasc Imaging. 2025 Jun.

. 2025 Jun;18(6):e018235.

doi: 10.1161/CIRCIMAGING.125.018235. Epub 2025 Mar 31.

Authors

Affiliations

¹ Department of Radiology, Medical University of Innsbruck, Austria (G.M.F., P.G.L.).
² Department of Cardiology, Leiden University Medical Center, the Netherlands (J.J.B., A.R.).
³ Division of Cardiovascular Medicine, Stanford University School of Medicine, Paolo Alto, CA (F.R.).
⁴ Department of Cardiovascular Medicine, Toho University Graduate School of Medicine, Tokyo, Japan (R.N.).
⁵ Department of Perioperative Cardiology and Cardiovascular Imaging, Centro Cardiologico Monzino Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Milan, Italy (G.P.).
⁶ Department of Biomedical, Surgical and Dental Sciences, University of Milan, Italy (G.P.).
⁷ Perioperative Cardiology and Cardiovascular Imaging Department, Centro Cardiologico Monzino IRCCS, Milan, Italy (S.M.).
⁸ Department of Nuclear Medicine, Cardiac Imaging, University Hospital and University of Zurich, Switzerland (R.R.B.).
⁹ Department of Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (C.G.).
¹⁰ Division of Cardiovascular Medicine, University of Virginia, Charlottesville (A.R.P., C.C.S.).
¹¹ Department of Cardiology and Radiology, George Washington University, Washington, DC (A.D.C., ).
¹² Department of Cardiology, Houston Methodist, TX (M.A.-M.,.).
¹³ Division of University Cardiology, IRCCS Galeazzi Sant'Ambrogio, Department of Biomedical and Clinical Sciences, University of Milan, Italy (D.A.).
¹⁴ Cardiovascular Research Foundation of Southern California, Cedars-Sinai Heart, David Geffen School of Medicine, University of California Los Angeles (R.P.K., G.C.).
¹⁵ Heart Institute, InCor, University of São Paulo Medical School, Brazil (C.E.R.).
¹⁶ Cardiac Center, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia (M. Alasnag).
¹⁷ Department of Cardiology, Rabin Medical Center, Petah Tikva and Tel Aviv University, Israel (A.H.).
¹⁸ IRCCS SYNLAB SDN, Naples, Italy (F.C.).
¹⁹ Department of Radiology, Istituto di Ricovero e Cura a Carattere (IRCCS) SYNLAB SDN, Naples, Italy (E. Maffei).
²⁰ UNICA, Unit of Cardiovascular Imaging, Hospital da Luz, Lisboa, Portugal (H.M., P.M.G.F).
²¹ Cardiac Imaging, Heart and Vascular Institute, Valley Health System, Paramus, NJ (H.G.).
²² Department of Radiology and Nuclear Medicine, German Heart Center Munich, Germany (M.H.).
²³ Division of Cardiovascular Imaging, St. Francis Hospital and Heart Center, Roslyn, NY (O.K.).
²⁴ Division of Cardiology, Department of Medicine, University of Louisville School of Medicine, KY (D.K.).
²⁵ Department of Cardiology, West Virginia University Heart and Vascular Institute, Morgantown (J.D.M.).
²⁶ Department of Cardiology and Department of Vascular Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands (N.S.N.).
²⁷ Department of Cardiology, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands (P.K.).
²⁸ The Lundquist Institute, Torrance, CA (M. Budoff).
²⁹ University of Tennessee Medical Center, Knoxville (K.S.).
³⁰ Division of Cardiology, MercyOne-Iowa Heart Center, Des Moines, IA (E. Martin).
³¹ Knight Cardiovascular Institute, Oregon Health & Science University, Portland (D.M.G., M.F.).
³² Allegheny Health Network Cardiovascular Institute, Allegheny Health Network, Pittsburgh, PA (A.C.O.).
³³ Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison (R.D.).
³⁴ Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison (P.N.).
³⁵ Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA (M.V.A., C.N.D.C.).
³⁶ Department of Radiology, Cardiovascular Imaging and Research Center, Massachusetts General Hospital and Harvard Medical School, Boston (B.F., J.M.B.).
³⁷ Minneapolis Heart Institute, MN (V.Y.C.).
³⁸ Division of Cardiology, Cardiovascular Clinical Trials, University of Washington, Seattle (K.B.).
³⁹ Heart and Vascular Institute, University of Pittsburgh Medical Center, PA (M. Bittencourt).
⁴⁰ National Institute of Cardiovascular Diseases, Karachi, Pakistan (S. Bhatti).
⁴¹ Piedmont Heart Institute, Atlanta, GA (V.P.).
⁴² Department of Cardiovascular Computed Tomography, Scripps Clinic, La Jolla, CA (G.W.).
⁴³ Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (R.C., R.B.).
⁴⁴ Medical Data Research Collaborative, United Kingdom (A.D.).
⁴⁵ Department of Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, MA (A.D.).
⁴⁶ Cardiology, Endeavor NorthShore Cardiovascular Institute, Evanston, IL (A.P.).
⁴⁷ Pritzker School of Medicine, University of Chicago, IL (A.P.).
⁴⁸ Department of Cardiac Imaging, Baylor Scott & White The Heart Hospital Plano, TX (A.A.).
⁴⁹ Midwest Heart and Vascular Associates, Kansas City, MO (S. Bloom).
⁵⁰ 1st Cardiology Department, Medical School, Aristotle University of Thessaloniki, Greece (V.K.).
⁵¹ Department of Cardiology, Angiology and Intensive Care Medicine, Deutsches Herzzentrum der Charité, Berlin, Germany (F.B.).
⁵² Cleerly Health, Denver, CO (M. Aquino).
⁵³ Department of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands (I.D.).

PMID: 40162910
PMCID: PMC12173162
DOI: 10.1161/CIRCIMAGING.125.018235

Abstract

Background: Coronary plaque features are imaging biomarkers of cardiovascular risk, but less is known about sex-specific patterns in their prognostic value. This study aimed to define sex differences in the coronary atherosclerotic phenotypes assessed by artificial intelligence-based quantitative computed tomography (AI-QCT) and the associated risk of major adverse cardiovascular events (MACEs).

Methods: Global multicenter registry including symptomatic patients with suspicion of coronary artery disease referred for coronary computed tomography angiography. AI-QCT analyzed 16 coronary artery disease features. The primary end point was MACE defined as death, myocardial infarction, late revascularization, cerebrovascular events, unstable angina, and congestive heart failure.

Results: Among 3551 patients (mean age, 59±12 years; 49.5% women), MACE occurred in 3.2% of women and 6.1% of men during an average follow-up of 4.8±2.2 years. The AI-QCT features total plaque volume, noncalcified plaque, calcified plaque, and percentage atheroma volume were significantly higher in men (P<0.001), and high-risk plaques were more prevalent (9.2% versus 2.5%; P<0.0001). Independent of age and cardiovascular risk factors, the AI-QCT-derived features of total plaque volume, noncalcified plaque, calcified plaque, and percentage atheroma volume conferred a higher relative risk of MACE in women than men. For every 50-mm³ increase in total plaque volume, relative risk increased by 17.7% (95% CI, 1.12-1.24) in women versus 5.3% (95% CI, 1.03-1.07) in men (P_interaction<0.001); for noncalcified plaque, relative risk increased by 27.1% (95% CI, 1.17-1.38) versus 11.6% (95% CI, 1.08-1.15; P_interaction=0.0015); and for calcified plaque, relative risk increased by 22.9% (95% CI, 1.14-1.33) versus 5.4% (95% CI, 1.01-1.10; P_interaction=0.0012), respectively. Similarly, for percentage atheroma volume, the risk was higher in women. The findings remained unchanged when restricted to a secondary composite end point (death and myocardial infarction).

Conclusions: The AI-QCT plaque features, total plaque volume, noncalcified plaque, calcified plaque, and percentage atheroma volume, conferred a higher relative MACE risk in women and may prompt more aggressive antiatherosclerotic therapy and reinforced preventive interventions.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04279496.

Keywords: artificial intelligence; atherosclerosis; computed tomography; computed tomography angiography; coronary artery disease; women’s health.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships that may be considered potential competing interests. Dr van Rosendael is a member of the Cleerly Scientific Advisory Board. Dr Pontone received an honorarium as a speaker/consultant and an institutional research grant from GE Healthcare, Bracco, Medtronic, and Novartis. Dr Buechel reports receiving speaking honoraria from GE Healthcare, Pfizer, Gilead, and IBA. Dr Gräni received funding from the Swiss National Science Foundation, InnoSuisse, the CAIM Foundation, the GAMBIT Foundation, and the Novartis Foundation for biomedical research, outside of the submitted work. Dr Choi is a consultant for Siemens, holds equity in Cleerly, and receives grant support from the George Washington Heart and Vascular Institute. Dr Rochitte reports receiving speaking honoraria for Pfizer, Edwards, GE, and Manole. Dr Khalique is a consultant for Edwards, Croivalve, and Restore Medical, holds equity in Triflo, and received honoraria for educational programs from Heartflow. Udo Hoffmann is an employee and equity holder in Cleerly, Inc, and received honoraria from Stanford University, Clinical Cardiovascular Sciences, Rapid AI, and MedTrace. Dr Danad is a member of the Cleerly Scientific Advisory Board. Dr Marques is a consultant for Cleerly, Inc. The other authors report no conflicts.

Figures

**Figure 1.**
**Predicted probability of major adverse cardiovascular event (MACE) in men vs women and forest plot. A**, Predicted probability by noncalcified plaque (NCP) volume. The probability of MACE increased higher for women compared with men, with an increasing absolute NCP (mm³) above a threshold of 180 mm³. The outer borders delineate the 95% CIs. B, Hazard ratios per 50-mm³ increment artificial intelligence–based quantitative computed tomography plaque volume increase for risk of MACE in women vs men (adjusted for age and cardiovascular [CV] risk factors). CP indicates calcified plaque (volume); and TPV, total plaque volume.

**Figure 2.**
**Case examples. A**, A 55-year-old woman with atypical chest pain and 2 cardiovascular risk factors (CVRFs): arterial hypertension, dyslipidemia, obesity, and hyperuricemia. Coronary computed tomography angiography (CTA) showed a noncalcified plaque (NCP) in the proximal left anterior descending (LAD) coronary artery (yellow arrow) with <50% diameter stenosis. Treatment with lipid-lowering therapy (statin+ezetimibe) and antihypertensive medication was initiated, and she remained event-free. **Right**, Artificial intelligence–based quantitative computed tomography (AI-QCT) plaque analysis showed an NCP volume of 155.4 mm³ (yellow box) and high-risk-plaque (HRP; red box) features. Note that color overlay (**mid**) facilitates the delineation of NCP and HRP. B, A 65-year-old woman with atypical chest pain, dyspnea, and a high coronary risk profile (5 CVRFs), smoking, arterial hypertension, positive family history, dyslipidemia, diabetes, and high lipoprotein A (89.1 ng/dL), who experienced major adverse cardiovascular event and underwent percutaneous coronary intervention (PCI) (LAD prox/mid/distal and right coronary artery [RCA]). Coronary CTA: white arrow pointing at calcified plaque in the proximal LAD. **Mid**, Curved multiplanar reformation. **Right**, AI-QCT plaque analysis revealed high total plaque volume (stage 3) with high calcified, high noncalcified plaque volume, and high percentage atheroma volume (39.2%).

See this image and copyright information in PMC

Comment in

Unfolding Evidence on Risk Stratification in Women Using Quantitative Atherosclerotic Plaque Measurements.
Shaw LJ, Lin FY. Shaw LJ, et al. Circ Cardiovasc Imaging. 2025 Jun;18(6):e018438. doi: 10.1161/CIRCIMAGING.125.018438. Epub 2025 May 30. Circ Cardiovasc Imaging. 2025. PMID: 40444358 No abstract available.

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AI-Quantitative CT Coronary Plaque Features Associate With a Higher Relative Risk in Women: CONFIRM2 Registry

Affiliations

AI-Quantitative CT Coronary Plaque Features Associate With a Higher Relative Risk in Women: CONFIRM2 Registry

Authors

Affiliations

Abstract

Conflict of interest statement

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Comment in

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Associated data

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