Here, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.
Compared with the control group, the ibrutinib group showed (1) a higher incidence and longer duration of AF with transesophageal burst stimulation; (2) increased left atrial mass, as indicated by echocardiography; (3) significant myocardial fibrosis in the left atrium on Masson trichrome staining; (4) Ca<sup>2+</sup> handling disorders in atrial myocytes, such as reduced Ca<sup>2+</sup> transient amplitude, enhanced spontaneous Ca<sup>2+</sup> release, and reduced sarcoplasmic Ca<sup>2+</sup> capacity; (5) enhanced delayed afterdepolarization in atrial myocytes; and (6) increased CaMKII expression and phosphorylation of RyR2-Ser2814 and PLN-Thr17.
We found that all patients had elevated RyR2 protein expression; however, a cohort of patients with AF had high miR-93, miR-106b, and miR-25 expression.
The RyR2-P2328S mutation produces catecholaminergic polymorphic ventricular tachycardia (CPVT) and AF in hearts from homozygous RyR2<sup>P2328S/P2328S</sup> (denoted RyR2<sup>S/S</sup>) mice.
In addition, JP2 can stabilize the expression of RyR2, whereas the deregulation of RyR2 expression may contribute to the pathogenesis of atrial fibrillation (AF).
These results also suggest that altered cytosolic Ca<sup>2+</sup> activation of RyR2 represents a common defect of RyR2 mutations associated with CPVT and AF, which could potentially be suppressed by carvedilol or (R)-carvedilol.
We conclude that the S4153R mutation is a gain-of-function RYR2 mutation associated with a clinical phenotype characterized by both CPVT and atrial fibrillation.
Knock-in mice with constitutively phosphorylated RyR2 at Ser2814 showed a higher incidence of Ca(2+) sparks and increased susceptibility to pacing-induced AF compared with controls.
Atrial tissue from both the AF dogs and humans with chronic AF showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel.