Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation

Post-operative atrial fibrillation (POAF) is a common complication after surgery, affecting ~30% of patients undergoing open-heart surgery. POAF-management remains challenging, partly due to incomplete understanding of underlying mechanisms. Although there is clinical evidence pointing to the presence of a pre-surgical vulnerable substrate contributing to POAF development, its nature and role in POAF development were largely unknown until now.

In an extensive multi-year effort with numerous international collaborators, Henry Sutanto and Jordi Heijman have provided new insight into the mechanisms of POAF. The study, which was published online in Circulation Research on July 30th, employed state-of-the-art biochemical and electrophysiological analyses in 265 human atrial samples and advanced in silico models to identify the presence of a subclinical pre-surgical atrial cardiomyopathy comprising NLRP3-inflammatory signaling and CaMKII-mediated calcium-handling changes that predispose POAF-patients to AF development. 

In addition, acute IL-1β stimulation activates a self-amplifying feed-forward loop promoting NLRP3-inflammasome activation and CaMKII-dependent RyR2 hyperphosphorylation, exacerbating proarrhythmic cardiomyocyte Ca2+-handling abnormalities. Thus, this preexisting substrate determines which atria will cross the AF threshold, initiating POAF, when acted upon by post-operative triggers. These observations provide a unifying model of AF involving a vulnerable substrate and inflammatory triggering that accounts for the transient occurrence of POAF post-operatively along with the high long-term AF recurrence rate in POAF patients.

Heijman J*, Muna AP*, Veleva T, Molina CE, Sutanto H, Tekook M, Wang Q, Abu-Taha I, Gorka M, Künzel S, El-Armouche A, Reichenspurner H, Kamler M, Nikolaev VO, Ravens U, Li N, Nattel S, Wehrens XHT, Dobrev D (2020) Atrial Myocyte NLRP3/CaMKII Nexus Forms a Substrate for Post-Operative Atrial Fibrillation. Circ Res. Epub July 30, 2020. *equally contributed first authors