IL-1 blockade in cardiovascular disease: an appraisal of the evidence across different inflammatory paradigms.

Abstract

Pre-clinical and clinical studies suggest a role for inflammation in the pathophysiology of cardiovascular (CV) diseases. The NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is activated during tissue injury and releases interleukin-1β (IL-1β). We describe three paradigms in which the NLRP3 inflammasome and IL-1β contribute to CV diseases. During acute myocardial infarction (AMI), necrotic cell debris, including IL-1α, induce NLRP3 inflammasome activation and further damage the myocardium contributing to heart failure (HF) (acute injury paradigm). In chronic HF, IL-1β is induced by persistent myocardial overload and injury, neurohumoral activation and systemic comorbidities favoring infiltration and activation of immune cells into the myocardium, microvascular inflammation, and a pro-fibrotic response (chronic inflammation paradigm). In recurrent pericarditis, an autoinflammatory response triggered by cell injury and maintained by the NLRP3 inflammasome/IL-1β axis is present (autoinflammatory disease paradigm). Anakinra, recombinant IL-1 receptor antagonist, inhibits the acute inflammatory response in patients with ST elevation myocardial infarction (STEMI) and acute HF. Canakinumab, IL-1β antibody, blunts systemic inflammation and prevents complications of atherosclerosis in stable patients with prior AMI. In chronic HF, anakinra reduces systemic inflammation and improves cardiorespiratory fitness. In recurrent pericarditis, anakinra and rilonacept, a soluble IL-1 receptor chimeric fusion protein blocking IL-1α and IL-1β, treat and prevent acute flares. In conclusion, the NLRP3 inflammasome and IL-1 contribute to the pathophysiology of CV diseases, and IL-1 blockade is beneficial with different roles in the acute injury, chronic inflammation and autoinflammatory disease paradigms. Further research is needed to guide the optimal use of IL-1 blockers in clinical practice.