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  • Review Article
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The LDL cumulative exposure hypothesis: evidence and practical applications

Nature Reviews Cardiology volume 21, pages 701–716 (2024)Cite this article

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Abstract

The trapping of LDL and other apolipoprotein B-containing lipoproteins within the artery wall causes atherosclerosis. As more LDL becomes trapped within the artery wall over time, the atherosclerotic plaque burden gradually increases, raising the risk of an acute cardiovascular event. Therefore, the biological effect of LDL on the risk of atherosclerotic cardiovascular disease (ASCVD) depends on both the magnitude and duration of exposure. Maintaining low levels of LDL-cholesterol (LDL-C) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and, by delaying the age at which mature atherosclerotic plaques develop, substantially reduces the lifetime risk of ASCVD events. Summing LDL-C measurements over time to calculate cumulative exposure to LDL generates a unique biomarker that captures both the magnitude and duration of exposure, which facilitates the estimation of the absolute risk of having an acute cardiovascular event at any point in time. Titrating LDL-C lowering to keep cumulative exposure to LDL below the threshold at which acute cardiovascular events occur can effectively prevent ASCVD. In this Review, we provide the first comprehensive overview of how the LDL cumulative exposure hypothesis can guide the prevention of ASCVD. We also discuss the benefits of maintaining lower LDL-C levels over time and how this knowledge can be used to inform clinical practice guidelines as well as to design novel primary prevention trials and ASCVD prevention programmes.

Key points

  • Atherosclerosis is caused by the trapping of LDL and other apolipoprotein B-containing lipoproteins within the artery wall over time, resulting in the progressive build-up of atherosclerotic plaque.

  • Summing the LDL-cholesterol (LDL-C) levels of an individual measured over time allows for an estimation of their cumulative exposure to LDL.

  • Cumulative exposure to LDL can be used as a biomarker to estimate the size of the accumulated plaque burden, track the rate of plaque progression and estimate the corresponding absolute risk of having an acute atherosclerotic cardiovascular event at any point in time.

  • Reducing the cumulative exposure to LDL reduces the number of atherogenic lipoproteins that become trapped within the artery wall, thus slowing the progression of atherosclerosis and substantially reducing the lifetime risk of atherosclerotic cardiovascular events.

  • The threshold for cumulative exposure to LDL and the corresponding accumulated plaque burden above which atherosclerotic cardiovascular events begin to occur depends on inherited predisposition and exposure to other causes of arterial wall injury, thus introducing the concept of a ‘personal plaque threshold’.

  • Cumulative exposure to LDL can be used as a therapeutic target to personalize prevention by titrating the reduction in LDL-C levels needed by each individual to slow the progression of atherosclerosis enough to keep their accumulated plaque burden below their personal plaque threshold.

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Fig. 1: Cumulative effect of LDL-C levels on plaque burden and corresponding absolute risk of atherosclerotic cardiovascular events.
Fig. 2: Trajectories of LDL-C and APOB levels in men and women over time.
Fig. 3: Cumulative lifetime exposure to LDL thresholds and lifetime risk of atherosclerotic cardiovascular events.
Fig. 4: Effect of other causes of arterial wall injury on LDL cumulative exposure thresholds.
Fig. 5: Median CAC score and lifetime risk of cardiovascular events by levels of cumulative exposure to LDL.
Fig. 6: Effect of timing and intensity of LDL-C lowering on cumulative lifetime exposure to LDL and cumulative lifetime risk of major atherosclerotic cardiovascular events.
Fig. 7: Design of a real-world, pragmatic, adaptive cluster-randomized trial to evaluate the benefit of reducing cumulative exposure to LDL to prevent atherosclerotic cardiovascular events.

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Acknowledgements

A.L.C. is supported in part by Ministero della Salute Ricerca Corrente.

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Authors and Affiliations

  1. DeepCausalAI Institute for Clinical Translation, Cambridge, UK

    Brian A. Ference

  2. TIMI Study Group, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Eugene Braunwald

  3. Department of Pharmacological and Biomolecular Sciences, University of Milano, Milan, Italy

    Alberico L. Catapano

  4. Multimedica IRCCS, Milan, Italy

    Alberico L. Catapano

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  1. Brian A. Ference
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  2. Eugene Braunwald
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  3. Alberico L. Catapano
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B.A.F. has received research grants and consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Eli Lilly, Novartis, Novo Nordisk, Pfizer, Regeneron and Sanofi. E.B. has received research support from AstraZeneca, Daiichi Sankyo, Merck and Novartis, and consulting fees from Amgen, Cardurion, MyoKardia, Novo Nordisk and Verve. A.L.C. has received honoraria, lecture fees or research grants from Aegerion, Amgen, Amryt, AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, Genzyme, Ionis Pharmaceutical, Kowa, Mediolanum, Medscape, Menarini, Merck, Mylan, Novartis, PeerVoice, Pfizer, Recordati, Regeneron, Sanofi, Sigma–Tau and The Corpus.

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Ference, B.A., Braunwald, E. & Catapano, A.L. The LDL cumulative exposure hypothesis: evidence and practical applications. Nat Rev Cardiol 21, 701–716 (2024). https://doi.org/10.1038/s41569-024-01039-5

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