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IMMUNE SYSTEM AND CVD IN 2018

Targeting inflammation in CVD: advances and challenges

Nature Reviews Cardiology volume 16, pages 74–75 (2019)Cite this article

Subjects

Considerable evidence supports a role for low-grade chronic inflammation in the atherothrombotic process, from plaque initiation to acute plaque rupture preceding myocardial infarction. Publications in 2018 revealed both the promise and challenges of targeting inflammation to treat atherosclerotic cardiovascular disease and highlighted the importance of understanding the mechanistic diversity of inflammatory pathways contributing to atherosclerosis.

Key advances

  • Selective neutralization of the cytokine IL-1β reduces cardiovascular disease events, particularly in individuals who achieved the highest reduction in inflammation as measured by high-sensitivity C-reactive protein (hsCRP) levels1.

  • Low-dose methotrexate does not protect against cardiovascular disease events and, interestingly, also does not reduce IL-1β, IL-6 or hsCRP levels in high-risk patients2.

  • Studies in mice indicate that a high-cholesterol diet can induce long-term reprogramming of haematopoietic reservoirs or ‘innate immune training’ to set the stage for higher inflammation via a mechanism involving IL-1β (ref.3).

  • Inflammation remains an important risk factor after levels of LDL cholesterol have been aggressively reduced, as is now possible with PCSK9 inhibitors in combination with other lipid-lowering therapies4.

In the past 2 decades, numerous studies have established that activation of both innate and adaptive immune responses in the setting of hypercholesterolaemia contribute to the development and progression of atherosclerosis. As a result, targeting inflammation for the primary and secondary prevention of atherosclerotic cardiovascular disease (CVD) has been an area of intense investigative focus. The past year has seen substantial advances in the development of immunotherapies for atherosclerosis, but has also revealed the challenging landscape ahead. Specifically, the results from two large-scale clinical trials — CANTOS1 and CIRT2 — demonstrated that different approaches to targeting inflammation can have dramatically different effects on cardiovascular risk reduction. A comparison of these trials provides a useful framework for guiding future drug development efforts in atherosclerotic CVD and points to a critical role for the cytokine IL-1β in the risk of CVD. In 2018, we also saw a new twist in our understanding of the mechanism of action of IL-1β, with the demonstration of a role for this cytokine in epigenetic reprogramming of immune cells to heighten the inflammatory response3, a process known as ‘innate immune training’. Finally, the question of whether inflammation remains an independent risk factor for atherothrombosis in the era of LDL-cholesterol (LDL-C) lowering to very low levels was addressed by a post-hoc analysis of two trials of PCSK9 inhibitors4.

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Acknowledgements

K.J.M.’s work is supported by the NIH (grants R35HL135799 and P01HL131478).

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Authors and Affiliations

  1. Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA

    Kathryn J. Moore

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  1. Kathryn J. Moore
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Correspondence to Kathryn J. Moore.

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The author declares no competing interests.

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Moore, K.J. Targeting inflammation in CVD: advances and challenges. Nat Rev Cardiol 16, 74–75 (2019). https://doi.org/10.1038/s41569-018-0144-3

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