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2018 - Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation

icon pap   Port-a-Patch publication in Circulation (2018)

Yao C., Veleva T., Scott L., Cao S., Li L., Chen G., Jeyabal P., Pan X., Alsina K.M., Abu-Taha I., Ghezelbash S., Reynolds C.L., Shen Y.H., LeMaire S.A., Schmitz W., Müller F.U., El-Armouche A., Eissa N.T., Beeton C., Nattel S. , Wehrens X.H.T., Dobrev D., Li N.

Circulation (2018) 0:CIRCULATIONAHA.118.035202 


Atrial fibrillation (AF) is frequently associated with enhanced inflammatory response. The “NACHT, LRR and PYD domain containing protein 3” (NLRP3)-inflammasome mediates caspase-1 activation and interleukin-1β release in immune cells, but is not known to play a role in cardiomyocytes (CMs). Here, we assessed the role of CM NLRP3-inflammasome in AF.


NLRP3-inflammasome activation was assessed by immunoblot in atrial whole-tissue lysates and CMs from patients with paroxysmal (pAF) or long-standing persistent (chronic) AF (cAF). To determine whether CM-specific activation of NLPR3 is sufficient to promote AF, a CM-specific knock-in mouse model expressing constitutively active NLRP3 (CM-KI) was
established. In vivo electrophysiology was used to assess atrial arrhythmia vulnerability. To evaluate the mechanism of AF, electrical activation pattern, Ca2+ spark frequency (CaSF), atrial
effective refractory period (AERP), and morphology of atria were evaluated in CM-KI mice and WT littermates.


NLRP3-inflammasome activity was increased in atrial CMs of pAF and cAF patients. CM-KI mice developed spontaneous premature atrial contractions and inducible AF, which was
attenuated by a specific NLRP3-inflammasome inhibitor, MCC950. CM-KI mice exhibited ectopic activity, abnormal sarcoplasmic-reticulum Ca2+-release, AERP shortening and atrial
hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of Nlrp3 suppressed AF development in CM-KI mice. Finally, genetic inhibition of Nlrp3 prevented AF
development in CREM transgenic mice, a well-characterized mouse model of spontaneous AF.


Our study establishes a novel pathophysiological role for CM NLRP3-inflammasome signaling with a mechanistic link to the pathogenesis of AF, and establishes inhibition of NLRP3 as a potential novel AF-therapy approach.

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