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Published on: June 29, 2022
Chronic kidney disease promotes atrial fibrillation via inflammasome pathway activation
Jia Song1, Jose Alberto Navarro-Garcia2,3, Jiao Wu4
1Department of Medicine (Cardiovascular Research).
Insights
Chronic kidney disease (CKD) increases atrial fibrillation (AF) risk by activating the NLRP3 inflammasome in the atria. Inhibiting NLRP3 or IL-1β reduces AF incidence and atrial remodeling in CKD models.
Area of Science:
- Cardiology
- Nephrology
- Immunology
Background:
- Chronic kidney disease (CKD) elevates atrial fibrillation (AF) risk, but the underlying mechanisms are unclear.
- The NLRP3 inflammasome and its effector IL-1β are implicated in inflammation-related conditions like AF and CKD.
- Elevated IL-1β levels and enhanced NLRP3 activity are observed in CKD patients with AF.
Purpose of the Study:
- To investigate the role of NLRP3/IL-1β signaling in the development of AF in the context of CKD.
- To determine if targeting NLRP3 or IL-1β can mitigate CKD-induced AF.
Main Methods:
- A mouse model of CKD was established using a subtotal nephrectomy protocol.
- Mice were genetically modified (Nlrp3-/-) or treated with anti-IL-1β antibodies to inhibit NLRP3 inflammasome activation.
- Cardiac structure, electrophysiology, and AF susceptibility were assessed in CKD and control groups.
Main Results:
- CKD induced elevated serum and atrial IL-1β levels, increased AF susceptibility, and prolonged AF duration in wild-type mice.
- CKD mice exhibited abbreviated atrial effective refractory periods, enlarged atria, and atrial fibrosis.
- Genetic NLRP3 inhibition or anti-IL-1β antibody treatment normalized atrial dimensions, reduced fibrosis, and decreased AF incidence.
Conclusions:
- CKD promotes AF development through NLRP3 inflammasome activation in the atria, leading to structural and electrical remodeling.
- Targeting the NLRP3/IL-1β pathway, particularly with IL-1β neutralizing antibodies, shows therapeutic potential for preventing CKD-induced AF.
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.
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