We propose that stabilizing ryanodine receptor type 2 (RyR2) may be a novel 
strategy for the treatment of atrial fibrillation (AF). Sarcoplasmic reticulum 
(SR) dysfunction caused by hyperphosphorylation of RyR2 and/or partial depletion 
of the stabilizing subunit calstabin2 has been indicated in AF. RyR2 
stabilization may prevent SR dysfunction and thereby protect the heart from 
damage. Hypertrophy, hyperthyroidism and heart failure, three common 
pathological conditions associated with AF, result in increased SR Ca(2+) leak 
via RyR2. RyR2 stabilization may prevent SR Ca(2+) leak and thereby prevent AF. 
Triggered activity appears to underlie atrial ectopic foci, which cause AF. 
Diastolic Ca(2+) leak from SR via RyR2 may initiate triggered activity. 
Therefore, modulating RyR2 opening probability would be predicted to protect 
against triggered activity. Atrial oxidative stress plays a contributing role in 
the pathogenesis of AF. RyR2 is a target of reactive oxygen species, and chronic 
RyR2 oxidation increases RyR2 opening probability in a more sustained, less 
reversible manner. Strategies that attenuate oxidative stress and protect 
against AF may also contribute to RyR2 stabilization. Finally, KN-3 and JTV519, 
two compounds that stabilize RyR2 in the closed state, prevent the induction of 
triggered activity and suppress the inducibility of sustained AF. Thus, it is 
reasonable to speculate that experimental approaches designed to improve RyR2 
stabilization will drive a novel conceptual revolution in AF drug development 
and lead to new clinical investigations.