A Mechanistic Clinical Trial Using ( R )- Versus (S )-Propafenone to Test RyR2 (Ryanodine Receptor) Inhibition for the Prevention of Atrial Fibrillation Induction

Abstract

Background: Experimental data suggest ryanodine receptor-mediated intracellular calcium leak is a mechanism for atrial fibrillation (AF), but evidence in humans is still needed. Propafenone is composed of two enantiomers that are equally potent sodium-channel blockers; however, (R )-propafenone is an ryanodine receptor inhibitor whereas (S )-propafenone is not. This study tested the hypothesis that ryanodine receptor inhibition with (R )-propafenone prevents induction of AF compared to (S )-propafenone or placebo in patients referred for AF ablation. Methods: Participants were randomized 4:4:1 to a one-time intravenous dose of (R )-propafenone, (S )-propafenone, or placebo. The study drug was given at the start of the procedure and an AF induction protocol using rapid atrial pacing was performed before ablation. The primary endpoint was 30 s of AF or atrial flutter. Results: A total of 193 participants were enrolled and 165 (85%) completed the study protocol (median age: 63 years, 58% male, 95% paroxysmal AF). Sustained AF and/or atrial flutter was induced in 60 participants (84.5%) receiving (R )-propafenone, 60 (80.0%) receiving (S )-propafenone group, and 12 (63.2%) receiving placebo. Atrial flutter occurred significantly more often in the (R )-propafenone (N=23, 32.4%) and (S )-propafenone (N=26, 34.7%) groups compared to placebo (N=1, 5.3%, P =0.029). There was no significant difference between (R )-propafenone and (S )-propafenone for the primary outcome of AF and/or atrial flutter induction in univariable ( P =0.522) or multivariable analysis ( P =0.199, adjusted for age and serum drug level). Conclusions: There is no difference in AF inducibility between (R )-propafenone and (S )-propafenone at clinically relevant concentrations. These results are confounded by a high rate of inducible atrial flutter due to sodium-channel blockade. Registration: https://clinicaltrials.gov ; Unique Identifier: NCT02710669.

The Role of RYR2 in Atrial Fibrillation

“…This reported case helps to strengthen the role of RYR2 as a disease gene in context of AF. The knowledge of RYR2 variants in patients with AF might become even more crucial for individual molecular therapies, as the RYR2 has already been identified as possible target of prevention and treatment of AF [ 19 , 20 ].…”

Targeting the RyR2 to Prevent Atrial Fibrillation

“…Current drugs known to inhibit RyR2 include propafenone, 12 flecainide, 14 carvedilol, 15,16 and dantrolene. 17 Shoemaker et al 18 undertook a well-designed mechanistic study to determine whether a single intravenous dose of the enantiomer (R)-propafenone, which inhibits RyR2, would prevent induction of AF compared to (S)-propafenone, which has no actions on RyR2, or placebo. 165 patients completed the study protocol before undergoing AF ablation.…”

Determinants and therapeutic potential of calcium handling abnormalities in atrial fibrillation: what can we learn from computer models?

“…The clinical impact of ectopic activity‐promoting Ca 2+ ‐handling abnormalities remains elusive and can at present not be directly evaluated in patients due to a lack of approved drugs specifically targeting individual Ca 2+ ‐handling abnormalities (Dobrev & Wehrens, 2017). Recent work revealed no significant difference in AF inducibility between ( R )‐propafenone, which inhibits the cardiac ryanodine receptor, and ( S )‐propafenone, which does not, in patients scheduled for AF ablation (Shoemaker et al., 2022). However, interpretation of these findings is challenging given the Na + ‐channel‐ and β‐adrenoceptor‐blocking effects of propafenone.…”