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INFLAMMATION

Inflammasome activation in AF

Inflammation is a well-known independent risk factor for atrial fibrillation (AF), but the causal role of inflammation in AF initiation and maintenance is not well understood. Now, Na Li and colleagues show that activation of the NLRP3 inflammasome in cardiomyocytes leads to electrophysiological abnormalities associated with the pathogenesis of AF. “To our knowledge, this is the first study to demonstrate a causal link between the NLRP3 inflammasome (an innate inflammation signalling complex) and the pathophysiology of AF,” says Li.

Li and colleagues found that the activity of the NLRP3 inflammasome was higher in atrial cardiomyocytes from patients with paroxysmal or long-lasting persistent AF than in cardiomyocytes from individuals in normal sinus rhythm and with no history of AF. Mice with a cardiomyocyte-specific knock-in of a constitutively active form of NLRP3 developed spontaneous premature atrial contractions and inducible AF, indicating that cardiomyocyte-specific activation of the NLPR3 inflammasome is sufficient to promote a substrate for AF. Constitutive activation of the NLPR3 inflammasome in cardiomyocytes promoted ectopic activity, abnormal calcium release from the sarcoplasmic reticulum, shortening of the atrial effective refractory period, and atrial hypertrophy. Treatment with an NLRP3 inflammasome-specific inhibitor attenuated AF development in these mice. Finally, cardiomyocyte-specific Nlrp3 knockdown prevented AF development in this mouse model and in a well-characterized mouse model of spontaneous AF.

“Our study establishes a link between the altered inflammasome activity in cardiomyocytes and the well-known electrophysiological changes and calcium mishandling associated with the pathogenesis of AF,” concludes Li. The research team plans to investigate the factors that lead to the activation of the cardiomyocyte NLRP3 inflammasome in AF and to evaluate this pathway as a potential therapeutic target for this condition.

References

Original article

  1. Yao, C. et al. Enhanced cardiomyocyte NLRP3 inflammasome signaling promotes atrial fibrillation. Circulation https://doi.org/10.1161/CIRCULATIONAHA.118.035202 (2018)

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Further reading

  1. Hu, Y. F. et al. Inflammation and the pathogenesis of atrial fibrillation. Nat. Rev. Cardiol. 12, 230–243 (2015)

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Correspondence to Irene Fernández-Ruiz.

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Fernández-Ruiz, I. Inflammasome activation in AF. Nat Rev Cardiol 15, 442 (2018). https://doi.org/10.1038/s41569-018-0045-5

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