Paul M Ridker is the Eugene Braunwald Professor of Medicine at the Harvard Medical School and directs the Center for Cardiovascular Disease Prevention, a translational research unit at the Brigham and Women’s Hospital in Boston. He is a graduate of Brown University (1981), the Harvard Medical School (1986), the Harvard School of Public Health (1992), and has received honorary medical degrees from several international institutions. As a preventive cardiologist, Dr. Ridker is best known for his work developing the inflammatory hypothesis of heart disease. His primary research brings together classical tools of large-scale, population-based epidemiology with emerging genetic and molecular techniques designed to improve the ability to predict and prevent vascular disease. Specific areas of interest involve inflammatory mechanisms of heart disease and molecular and genetic determinants of haemostasis, thrombosis, and inflammation with a focus on “predictive medicine”, early disease diagnosis, and the underlying causes and prevention of acute coronary syndromes. Dr Ridker was the Principal Investigator of the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) and the NHLBI funded Cardiovascular Inflammation Reduction Trial (CIRT).
Tuesday 28 May 13:00
Inflammation inhibition and atherothrombosis
Despite the fact that inflammatory infiltration by white blood cells is critical to the atherosclerotic process, this was until recently regarded as secondary to the causative insults of high concentrations of apolipoprotein B (apoB)-containing lipoproteins, high blood pressure, high blood glucose and environmental toxins. Preventive efforts targeting major cardiovascular risk factors, in particular low-density lipoprotein cholesterol (LDL-C), the major apoB-containing lipoprotein, have had success in reducing cardiovascular events. Yet even with best evidence-based therapeutic approaches and lowering LDL-C beyond guideline-recommended levels with novel PCSK9-targeted therapeutics, a high residual cardiovascular risk persists.
Inflammation was proposed as a potential contributor to this risk, supported by mechanistic evidence for the involvement of both the innate and adaptive immune system in atherothrombosis, as well as epidemiological evidence linking inflammatory biomarkers (such as interleukin-6 [IL-6], fibrinogen, and C-reactive protein) with cardiovascular risk. Subsequently, results from the CANTOS trial provided proof-of-concept evidence that targeting inflammatory mediators with canakinumab reduced cardiovascular events, against a background of well controlled LDL-C levels. The effects of canakinumab were not only mediated by targeted neutralization of IL-1β, a pro-inflammatory cytokine with multiple roles in the atherothrombotic process, but also by downstream effects mediated by other inflammatory cytokines including IL-6. Thus, accumulating evidence underlines the importance of inflammation, both as a core driver of atherogenesis, and as a contributor to all phases of the atherothrombotic process, from early endothelial dysfunction through to the clinical sequelae associated with plaque rupture and erosion.
The findings from CANTOS offer a new perspective for personalized approaches to cardiovascular risk reduction, targeting interventions according to the risk profile of individual patients.
Libby P, Loscalzo J, Ridker PM, Farkouh ME, Hsue PY, Fuster V, Hasan AA, Amar S. Inflammation, immunity, and infection in atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol 2018;72:2071-81.
Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J 2018;39:3499-507.
Ridker PM. Interleukin-1 inhibition and ischaemic stroke: has the time for a major outcomes trial arrived? Eur Heart J 2018;39:3518-20.
Aday AW, Ridker PM. Antiinflammatory therapy in clinical care: the CANTOS Trial and beyond. Front Cardiovasc Med 2018;5:62.