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.

The Role of Immune Cells Driving Electropathology and Atrial Fibrillation

“…New anti-inflammatory and antioxidant therapies are explored in an increasing number of studies. The injection of IL-1β antibodies to neutralize circulating IL-1β prevents cardiac structural remodeling and reduces the incidence of AF in a mouse model of chronic kidney disease [145]. Etanercept, a TNFα inhibitor, prevents atrial arrhythmias induced after 6 weeks of swimming exercise in a mouse model and reduces atrial structural remodeling and AF vulnerability [146].…”

A High-Protein Diet Promotes Atrial Arrhythmogenesis via Absent-in-Melanoma 2 Inflammasome

“…Programmed electrical stimulation (PES) was performed to determine cardiac electrophysiological differences among treatment groups using the previously published protocols [14,16,26,27]. Briefly, mice were anesthetized with a 1.5% isoflurane/oxygen mixture.…”

“…Systolic cardiac function was assessed by echocardiography using VisualSonics Vevo F2 Ultrasound (FujiFilm VisualSonics, Toronto, ON, Canada) as described previously [14,16,26]. Briefly, mice were anesthetized using 1.5-2% isoflurane mixed with 100% O 2 and placed on a heated platform, with their four limbs taped to ECG electrodes.…”

“…Atrial myocytes were isolated as described [14,16,26,27]. Mouse hearts, harvested during anesthesia, were cannulated and perfused in Langendorff mode with Ca 2+ -free Tyrode solution for 1-3 min at 37 • C, followed by 0.022 mg/mL Liberase (TH Research Grade, Sigma-Aldrich, St. Louis, MO, USA, 5401151001) in Ca 2+ -free Tyrode at 37 • C until digestion was complete.…”

“…Previously, we showed that NLRP3 inflammasome activation in atrial tissue is involved in AF pathogenesis and mediates atrial arrhythmogenesis in the context of obesity or chronic kidney disease [14,16,27]. To determine the impact of HPD on atrial arrhythmogenesis and whether the NLRP3 inflammasome plays a role, we first subjected WT and Nlrp3 −/− to NC and HPD, respectively, for 4 weeks.…”