The intracellular sensing
protein termed NLRP3 (for
NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3
inflammasome. The NLRP3
inflammasome plays a major role in
inflammation, particularly in the production of IL (interleukin)-1β. IL-1β is the most studied of the
IL-1 family of
cytokines, including 11 members, among which are IL-1α and
IL-18. Here, we summarize preclinical and clinical findings supporting the key pathogenetic role of the NLRP3
inflammasome and
IL-1 cytokines in the formation, progression, and complications of
atherosclerosis, in ischemic (acute
myocardial infarction), and nonischemic injury to the myocardium (
myocarditis) and the progression to
heart failure. We also review the clinically available
IL-1 inhibitors, although not currently approved for cardiovascular indications, and discuss other
IL-1 inhibitors, not currently approved, as well as oral NLRP3
inflammasome inhibitors currently in clinical development.
Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior acute
myocardial infarction in a large phase III clinical trial, including 10 061 patients world-wide. Phase II clinical trials show promising data with
anakinra, recombinant
IL-1 receptor antagonist, in patients with ST-segment-elevation acute
myocardial infarction or
heart failure with reduced ejection fraction.
Anakinra also improved outcomes in patients with
pericarditis, and it is now considered standard of care as second-line treatment for patients with recurrent/refractory
pericarditis.
Rilonacept, a soluble
IL-1 receptor chimeric fusion
protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/refractory
pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3
inflammasome and the
IL-1 cytokines with the pathogenesis of
cardiovascular diseases. The future will likely include targeted inhibitors to block the
IL-1 isoforms, and possibly oral NLRP3
inflammasome inhibitors, across a wide spectrum of
cardiovascular diseases.