Sterile Inflammation as a Novel Therapeutic Target to Heart Failure

Abstract

There is substantial evidence that chronic heart failure is associated with inflammation. Ischemic stress such as myocardial infarction lead to necrotic cell death and release of damage associated molecular patterns（DAMPs），factors that signal cell damage and induce expression of proinflammatory chemokines and cytokines. It has recently become evident that nonischemic interventions are also associated with increases in inflammatory genes and immune cell accumulation in the heart and that these contribute to fibrosis and ventricular dysfunction. In this review we provide recent evidence of adverse cardiac remodeling induced by sterile inflammation in response to nonischemic stress. We also introduce the role of the multifunctional Ca2+/calmodulin-dependent protein kinase, CaMKII, as a transducer of stress signals to nuclear factor-B activation, expression of proinflammatory cytokines and chemokines, and priming and activation of the NOD-like pyrin domain-containing protein 3（NLRP3）inflammasome in cardiomyocytes. The potential efficacy of anti-inflammatory therapy was shown by the results of the recently published clinical trials in which a significant decrease in adverse cardiac events was observed in patients treated by inhibitions of mediators generated through the NLRP3 inflammasome, suggesting that the inflammasome plays a central role in both initiating and sustaining cardiac sterile inflammation. Achieving a further understanding of these mechanisms has implications for the development of therapeutic regimens to limit cardiac remodeling.