Evaluating the Role of Lipoprotein(a) in Enhancing Risk Stratification for the Presence and Extent of Subclinical Coronary Artery Disease Burden - A BioHEART-CT Study

Sina Fathieh^{1

2

3}, Owen Tang^{1

2}, Michael P Gray^{1

2}, Christian Zanchin¹, Stephen T Vernon^{1

2}, Elijah Genetzakis^{1

2}, Collin Tran^{1

4}, David R Sullivan^{1

4

5}, Stephen J Nicholls⁶, David S Celermajer^{1

7

8}, Peter J Psaltis^{9

10

11}, Stuart M Grieve^{1

3

12}, Gemma A Figtree^{1

2

13}

Affiliations

¹ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
² Cardiovascular Discovery Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia.
³ Imaging and Phenotyping Laboratory, Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
⁴ Department of Chemical Pathology, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown NSW 2050.
⁵ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
⁶ Victorian Heart Institute, Monash University, Melbourne, Australia.
⁷ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁸ Heart Research Institute, Sydney.
⁹ Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
¹⁰ Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.
¹¹ Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.
¹² Lumus Imaging, St George Private Hospital, Kogarah NSW 2217.
¹³ Department of Cardiology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, Australia.

PMID: 40458002
DOI: 10.1093/eurjpc/zwaf323

Evaluating the Role of Lipoprotein(a) in Enhancing Risk Stratification for the Presence and Extent of Subclinical Coronary Artery Disease Burden - A BioHEART-CT Study

Sina Fathieh et al. Eur J Prev Cardiol. 2025.

. 2025 Jun 3:zwaf323.

doi: 10.1093/eurjpc/zwaf323. Online ahead of print.

Authors

Affiliations

¹ School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
² Cardiovascular Discovery Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia.
³ Imaging and Phenotyping Laboratory, Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2006, Australia.
⁴ Department of Chemical Pathology, NSW Health Pathology, Royal Prince Alfred Hospital, Camperdown NSW 2050.
⁵ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
⁶ Victorian Heart Institute, Monash University, Melbourne, Australia.
⁷ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁸ Heart Research Institute, Sydney.
⁹ Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, Australia.
¹⁰ Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, Australia.
¹¹ Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.
¹² Lumus Imaging, St George Private Hospital, Kogarah NSW 2217.
¹³ Department of Cardiology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, Australia.

PMID: 40458002
DOI: 10.1093/eurjpc/zwaf323

Abstract

Aims: Lipoprotein(a) [Lp(a)] has regained attention as an independent cardiovascular risk factor, particularly given emerging therapies entering late-phase clinical trials. Here, we aim to examine the association of Lp(a) with CAD and the potential of Lp(a) as an enrichment criterion for identifying individuals more likely to benefit from screening for subclinical CAD with CT imaging.

Methods: We analysed data from 1,718 adults undergoing CTCA for suspected CAD enrolled in the BioHEART study. Lp(a) levels were measured, and CAD burden was assessed using coronary artery calcium score (CACS) and Gensini scores. Plaque morphology for the most stenotic plaque of each Gensini segment was classified as calcified, non-calcified or mixed. Youden's index with 10,000 bootstraps was used to identify the optimal threshold for increased risk of clinically actionable CAD.

Results: Lp(a) was strongly associated with all CTCA measures of CAD examined. Elevated Lp(a) above 22 nmol/L was linked to more advanced multi-segment (ordinal OR = 1.14 [1.03-1.25]) and multivessel disease (ordinal OR = 1.11 [1.02-1.20]), with a 2.6% increased risk of a CACS >100 for every 10 nmol/L increment. Lp(a) was most strongly associated with mixed plaque burden even after adjusting for traditional risk factors (β = 4.75, p=0.001), but not with non-calcified or calcified plaque. Adding Lp(a) to standard risk models resulted in an overall NRI of 16% [0.06-0.27] and 42% [0.16-0.70] in patients without standard modifiable risk factors.

Conclusion: Our findings suggest Lp(a)'s role in a new clinical pathway: screening patients considered low or intermediate risk, particularly those without standard modifiable risk factors for non-invasive imaging to detect subclinicalCAD.

Keywords: CT coronary angiography; Coronary artery disease; Lipoprotein(a); SMuRFless; biomarker.

Plain language summary

Our study confirms Lp(a) as an independent risk factor for CAD measured in a stable cohort undergoing CTCA for screening or symptoms suggestive of CAD, likely resulting in more aggressive and advanced phenotypes over time. Its addition to screening and risk prediction models should become a part of standard clinical practice. Lp(a) and higher-risk plaque phenotype: Elevated Lp(a) is associated with more extensive multi-segment and multivessel disease and a higher prevalence of mixed plaques. A 10 nmol/L increase beyond the 22 nmol/L cutoff raises clinically actionable CAD risk by 2.6%.Lp(a) as a non-invasive early screening tool for CAD: Integrating Lp(a) with traditional risk models significantly improves the prediction of CTCA-determined clinically-actionable CAD, particularly in low and intermediate -risk groups, supporting its use in routine screening and triaging for early CT imaging. Our optimal diagnostic cutoff is less than quarter of the currently used threshold in clinical practice.

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Evaluating the Role of Lipoprotein(a) in Enhancing Risk Stratification for the Presence and Extent of Subclinical Coronary Artery Disease Burden - A BioHEART-CT Study

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Evaluating the Role of Lipoprotein(a) in Enhancing Risk Stratification for the Presence and Extent of Subclinical Coronary Artery Disease Burden - A BioHEART-CT Study

Authors

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Abstract

Plain language summary

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