Ridker, Paul

Paul Ridker

Boston, USA

Paul M. Ridker is Director of the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital and the Eugene Braunwald Professor of Medicine at Harvard School of Medicine (HMS). His clinical interests include coronary artery disease and the underlying causes and prevention of atherosclerotic disease. His research focuses on inflammatory mediators of heart disease and the molecular and genetic epidemiology of haemostasis and thrombosis, with particular interests in biomarkers for coronary disease, “predictive” medicine, and the underlying causes and prevention of atherosclerotic disease.

Wednesday 25 May

Should we target inflammation?

Chair:
  • Maciej Banach
  • Christoph Binder

Systemic vascular inflammation plays a central role in all stages of atherosclerosis, from initiation to the progression and destabilization of atheroma, and consequent development of acute coronary syndromes. Although understanding of the underlying biology of inflammation has increased, translation into effective therapies has proved challenging. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) provided proof of the concept that targeting IL (interleukin)-1β, an major cytokine involved in activation of proinflammatory signalling pathways, reduced cardiovascular events in high-risk patients with established atherosclerotic disease. Subsequent to CANTOS, clinical trials have confirmed the benefits of another anti-inflammatory therapy, colchicine in patients with a recent myocardial infarction or with chronic coronary syndromes. However, not all trials have been positive. In CIRT (Cardiovascular Inflammation Reduction Trial), treatment with low-dose methotrexate, a widely used therapy for inflammatory conditions, was not associated with fewer cardiovascular events than placebo due to lack of effect on levels of interleukin-1β, interleukin-6, or C-reactive protein.

Taken together these findings imply considering both the relevance of the patient population – targeting treatment to patients with sufficiently elevated inflammation  – and the diversity of inflammatory pathways involved in atherosclerosis. Thus, while residual inflammatory risk is increasingly recognised as a viable therapeutic target, identifying which inflammatory pathways are preferable targets for intervention requires clarification. Moreover, despite evidence for the clinical utility of high-sensitivity C-reactive protein, it may not be the ideal target for anti-inflammatory therapies.

Recent insights suggest that targeting the NLRP3 inflammasome pathway, which plays a central role in atherosclerosis and the pathogenesis of heart disease, may offer therapeutic potential. Animal models have demonstrated protective effects from NLRP3 inflammasome inhibition, and early clinical data for selective inhibitors of the NLRP3 inflammasome supported this as a feasible and effective strategy. Realizing the promise of targeting inflammation will likely require more individualized approaches targeting different contributors to residual inflammatory risk.

References

Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M; RESCUE Investigators. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021;397:2060-2069.

Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021;128:1728-1746.

Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, Dey AK, Libby P, Tabas IA, Mehta NN, Ridker PM. The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J 2021;42:896-903.


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May 22-25, 2022 - EAS Congress