Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes. In this Review, the authors provide an overview of the immune cells involved in atherosclerosis, discuss preclinical research and published and ongoing clinical trials assessing the therapeutic potential of targeting the immune system in atherosclerosis, highlight emerging therapeutic targets from preclinical studies and identify challenges for successful clinical translation. Inflammation is an important component of the pathophysiology of cardiovascular disease; an imbalance between pro-inflammatory and anti-inflammatory processes drives chronic inflammation and the formation of atherosclerotic plaques in the vessel wall. Clinical trials assessing canakinumab and colchicine therapies in atherosclerotic cardiovascular disease have provided proof-of-principle of the benefits associated with therapeutic targeting of the immune system in atherosclerosis. The immunosuppressive adverse effects associated with the systemic use of anti-inflammatory drugs can be minimized through targeted delivery of anti-inflammatory drugs to the atherosclerotic plaque, defining the window of opportunity for treatment and identifying more specific targets for cardiovascular inflammation. Implementing immunophenotyping in clinical trials in patients with atherosclerotic cardiovascular disease will allow the identification of immune signatures and the selection of patients with the highest probability of deriving benefit from a specific therapy. Clinical stratification via novel risk factors and discovery of new surrogate markers of vascular inflammation are crucial for identifying new immunotherapeutic targets and their successful translation into the clinic. Inflammation is an important component of the pathophysiology of cardiovascular disease; an imbalance between pro-inflammatory and anti-inflammatory processes drives chronic inflammation and the formation of atherosclerotic plaques in the vessel wall. Clinical trials assessing canakinumab and colchicine therapies in atherosclerotic cardiovascular disease have provided proof-of-principle of the benefits associated with therapeutic targeting of the immune system in atherosclerosis. The immunosuppressive adverse effects associated with the systemic use of anti-inflammatory drugs can be minimized through targeted delivery of anti-inflammatory drugs to the atherosclerotic plaque, defining the window of opportunity for treatment and identifying more specific targets for cardiovascular inflammation. Implementing immunophenotyping in clinical trials in patients with atherosclerotic cardiovascular disease will allow the identification of immune signatures and the selection of patients with the highest probability of deriving benefit from a specific therapy. Clinical stratification via novel risk factors and discovery of new surrogate markers of vascular inflammation are crucial for identifying new immunotherapeutic targets and their successful translation into the clinic.