Enhanced Cardiomyocyte NLRP3 Inflammasome Signaling Promotes Atrial Fibrillation

Abstract

-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, Ca 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 Ca-release, AERP shortening and atrial hypertrophy. Adeno-associated virus subtype-9 mediated CM-specific knockdown of suppressed AF development in CM-KI mice. Finally, genetic inhibition of 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.

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions

“…In addition, as already described (Fig. 3), histological analysis did not reveal increased LA fibrosis in the sham group, as would be expected in rats exposed to systemic inflammation 31,32 .…”

“…This intriguing finding led us to several additional experiments in order to try to reveal possible source\s for this phenomenon. The results strongly argue against the involvement of systemic inflammation as an underlying mechanism based on direct serum measurements of inflammatory cytokines as well as the absence of atrial fibrosis which is expected to occur in the presence of systemic inflammation 31,32,46 . Post-operative AF due to the thoracotomy we performed in the implantation surgery is another option that should be considered.…”

CYP2J2/EET reduces vulnerability to atrial fibrillation in chronic pressure overload mice

“…Besides that, emerging evidence indicated enhanced inflammatory responses in patients with AF and accompanied by increased circulating levels of pro‐inflammatory cytokines . Further, NLRP3 inflammasome activation was recently shown to be involved in the pathogenesis of AF . Because AF is able to exacerbate inflammation and atrial fibrosis that further perpetuates the arrhythmia, reduction of inflammation and reversal of structural remodelling have increasingly become the focus of new therapeutic strategies for the prevention of AF …”

Nod-like Receptor Protein 3 (Nlrp3) Inflammasomes Inhibition by Metformin Limits Myocardial Ischemia/reperfusion Injury

“…NOD-like receptor protein 3 (NOD-like receptor protein 3, NLRP3) inflammasome, as a participant of the inflammatory immune response, is closely related to cardiovascular diseases [20]. Numerous studies have confirmed that NLRP3 inflammasome is involved in the occurrence and development of myocardial I/R injury, cardiomyopathy, arrhythmia, and other diseases [21][22][23]. However, there are no reports on the role of NLRP3 inflammasome activation in myocardial I/R injury and metformin-related intervention studies.…”