Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation
Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K. Lahiri, Joshua A. Keefe, Yuriana Aguilar-Sanchez, Oliver M. Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E. Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S. Thomas, Dobromir Dobrev, Xander H.T. Wehrens, Na Li
Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K. Lahiri, Joshua A. Keefe, Yuriana Aguilar-Sanchez, Oliver M. Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E. Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S. Thomas, Dobromir Dobrev, Xander H.T. Wehrens, Na Li
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Research Article Cardiology

Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation

Abstract

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain–containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3–/– and WT mice were subjected to a 2-stage subtotal nephrectomy protocol to induce CKD. Four weeks after surgery, IL-1β levels in serum and atrial tissue were increased in WT CKD (WT-CKD) mice versus sham-operated WT (WT-sham) mice. The increased susceptibility to pacing-induced AF and the longer AF duration in WT-CKD mice were associated with an abbreviated atrial effective refractory period, enlarged atria, and atrial fibrosis. Genetic inhibition of NLRP3 in Nlrp3–/– mice or neutralizing anti–IL-1β antibodies effectively reduced IL-1β levels, normalized left atrial dimensions, and reduced fibrosis and the incidence of AF. These data suggest that CKD creates a substrate for AF development by activating the NLRP3 inflammasome in atria, which is associated with structural and electrical remodeling. Neutralizing IL-1β antibodies may be beneficial in preventing CKD-induced AF.

Authors

Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K. Lahiri, Joshua A. Keefe, Yuriana Aguilar-Sanchez, Oliver M. Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E. Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S. Thomas, Dobromir Dobrev, Xander H.T. Wehrens, Na Li

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Figure 7

Neutralization of circulating IL-1β attenuates CKD-induced atrial arrhythmogenesis.

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Neutralization of circulating IL-1β attenuates CKD-induced atrial arrhyt...
(A) Serum levels of IL-1β in WT mice 2 and 3 weeks after sham or CKD surgeries. (B) Timeline of anti–IL-1β antibody (5 mg/kg, i.p.) or IgG (as a control) injections into WT-CKD mice. 2/3 Nx, two-thirds nephrectomy. Panel B was created with BioRender.com. (C and D) Representative echocardiographic long-axis views of the heart (C) and quantification of the LA area (D) in WT-CKD mice that received IgG or anti–IL-1β antibody injections. Blue outlined areas indicate the LA. Scale bar: 3 mm. (E) Serum levels of IL-1β in WT-CKD mice that received IgG or anti–IL-1β antibody injections following the CKD procedure. (F and G) Representative Western blots (F) and quantification (G) of IL-1β in atrial tissue of WT-CKD mice after 3 weekly injections of IgG or anti–IL-1β antibody. (H and I) Representative images (H) of Masson’s trichrome staining in atria and quantification of atrial fibrosis (I) in WT-CKD mice after 3 weekly injections of IgG or anti–IL-1β antibody. Scale bar: 200 μm. (J–L) Representative lead 2 surface ECG and intracardial ECG recordings (J), incidence (K), and duration (L) of pacing-induced AF in WT-CKD mice after 3 injections of IgG or anti–IL-1β antibody. Scale bar: 200 ms (J). Data are expressed as the mean ± SEM in A, D, E, G, I, and L, and as a percentage in K. *P < 0.05 and ***P < 0.001, by unpaired, 2-tailed Student’s t test (A, D, E, G, and I), Fisher’s exact test (K), and Mann-Whitney U test (L).