Author + information
- Received September 17, 2018
- Revision received December 20, 2018
- Accepted December 30, 2018
- Published online April 1, 2019.
- Tian X. Zhao, MD, MPhil and
- Ziad Mallat, MD, PhD∗ ()
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom
- ↵∗Address for correspondence:
Dr. Ziad Mallat, Division of Cardiovascular Medicine, University of Cambridge, West Forvie Building, Robinson Way, Cambridge CB2 0SZ, United Kingdom.
• Atherosclerosis is an inflammatory disease. However, this hypothesis remained unproved in the clinic due to the failure of previously attempted anti-inflammatory therapies in reducing cardiovascular events.
• Reasons for the previous failures include redundant inflammatory pathways, overlap with pathways targeted by existing therapies, and little support for a causal role of the targeted pathways in genetic studies.
• CANTOS showed that selective targeting of inflammation through inhibition of IL-1β improves cardiovascular outcomes. Several therapies targeting the innate and the adaptive arms of the immune system are currently in clinical trials.
• It is important to reconsider and improve the relevance of animal models of atherosclerosis to the human disease. The use of humans as model organisms should improve and accelerate target selection and translation.
Atherosclerosis has long been known as an inflammatory disease. However, whether targeting inflammation improves outcomes was unproven until the recent results of CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study). In this review, we reflect on why it has taken a long time to prove the inflammatory hypothesis of atherosclerosis and derive important lessons for the future. In particular, we discuss the off-target immune-modulatory effects of approved cardiovascular therapies, review the attempted anti-inflammatory therapies including the recently published CIRT (Cardiovascular Inflammation Reduction Trial), and discuss the likely reasons for their failures. We further build on CANTOS to review the immune-modulatory therapies for atherosclerosis currently in trials, and discuss the likelihood of their added value as well as the potential hazard associated with their use. We finally argue for a critical approach to the use of animal models, coupled with the use of humans as model organisms to accelerate the identification of the most appropriate targets.
Dr. Zhao has received funding through a Medical Research Council, Developmental Pathway Funding Scheme. Dr. Mallat has received funding support from the British Heart Foundation for his BHF Chair.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received September 17, 2018.
- Revision received December 20, 2018.
- Accepted December 30, 2018.
- 2019 American College of Cardiology Foundation
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