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A Review of 'Inflammation Drives Atherosclerosis from Beginning to End'

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Dr. Peter Libby delivered the Eugene Braunwald Keynote Lecture “Inflammation Drives Atherosclerosis from Beginning to End” on Monday, April 4, 2022, at the American College of Cardiology Scientific Sessions held in Washington, D.C. Dr. Libby traced the evolution of theories of atherogenesis that ranged from viewing atherosclerosis as a lipid storage disease, then as a bland proliferative lesion of smooth muscle cells, to the current concept of a process that intimately involves inflammation.

Recruitment of inflammatory leukocytes to the arterial intima is integral in initiating steps in forming atherosclerotic lesions. As this chronic disease takes root, there is a tug-of-war between pro-inflammatory, anti-inflammatory, and pro-resolving mediators. Ultimately, the most dramatic manifestations of atherosclerosis, the acute coronary syndromes, result from plaque disruptions and thrombosis.

Dr. Libby reviewed the pathophysiology of plaque rupture that involves modulation by inflammatory mediators of the metabolism of interstitial collagen that lends strength to the lesion’s protective fibrous cap that fails in plaque rupture and thrombosis, the most common cause of fatal acute coronary infarction. He also described work from his laboratory implicating other limbs of inflammation in superficial erosion, another common cause of coronary thrombosis.

Dr. Libby described work from his laboratory, which started in the 1980s, that implicated pro-inflammatory cytokines in altering the behavior of artery wall cells and linked inflammatory cells to the pathophysiology of atherosclerosis. His laboratory described the inducible expression of interleukin-1 (IL-1) in human vascular endothelial and smooth muscle cells. They discovered the auto-induction of IL-1 in the vasculature. Subsequent work in his group showed that IL-1 could induce IL-6, another cytokine strongly implicated as causal in human atherothrombotic events, by contemporary human genetic studies.

Having worked out these pathways, Dr. Libby instigated and helped conduct trials that targeted inflammation by neutralizing IL-1β, implicated in atherogenesis in his early work. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was the first large-scale trial that proved the inflammation hypothesis of atherosclerosis in humans. Current clinical trials target IL-6, which Dr. Libby’s laboratory has long been implicated in atherosclerosis.

Thus, inflammation is involved in the pathogenesis of atherosclerosis from its very inception through to its thrombotic complications. Inflammation is now a viable target for intervention, as shown by CANTOS and studies targeting inflammation with colchicine. Studies underway targeting other inflammatory mediators such as IL-6 promise to advance the ability of cardiologists to manipulate inflammation to reduce cardiovascular events.

Dr. Libby is employed by Brigham and Women’s Hospital. He has received the following grants: NIH/NHLBI 5R01HL134892-02; NIH/NHLBI R01HL137913-04; AHA 18CSA34080399. He was an unpaid consultant to, or involved in clinical trials for: Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Novo Nordisk, Novartis, Pfizer, Sanofi-Regeneron and has been a member of the scientific advisory board for: Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, and XBiotech, Inc. He has also served on the Board of Directors of XBiotech, Inc. Dr. Libby has a financial interest in Xbiotech. Dr. Libby's interests were reviewed and are managed by Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Illustration by April Brust

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