Emerging Antiarrhythmic Drugs for Atrial Fibrillation

Abstract

Atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is driven by complex mechanisms that differ between subgroups of patients. This complexity is apparent from the different forms in which AF presents itself (post-operative, paroxysmal and persistent), each with heterogeneous patterns and variable progression. Our current understanding of the mechanisms responsible for initiation, maintenance and progression of the different forms of AF has increased significantly in recent years. Nevertheless, antiarrhythmic drugs for the management of AF have not been developed based on the underlying arrhythmia mechanisms and none of the currently used drugs were specifically developed to target AF. With the increased knowledge on the mechanisms underlying different forms of AF, new opportunities for developing more effective and safer AF therapies are emerging. In this review, we provide an overview of potential novel antiarrhythmic approaches based on the underlying mechanisms of AF, focusing both on the development of novel antiarrhythmic agents and on the possibility of repurposing already marketed drugs. In addition, we discuss the opportunity of targeting some of the key players involved in the underlying AF mechanisms, such as ryanodine receptor type-2 (RyR2) channels and atrial-selective K⁺-currents (I_K2P and I_SK) for antiarrhythmic therapy. In addition, we highlight the opportunities for targeting components of inflammatory signaling (e.g., the NLRP3-inflammasome) and upstream mechanisms targeting fibroblast function to prevent structural remodeling and progression of AF. Finally, we critically appraise emerging antiarrhythmic drug principles and future directions for antiarrhythmic drug development, as well as their potential for improving AF management.

Keywords: atrial fibrillation; ectopic activity; fibroblast; pharmacology.

Figure 1

Key pathways for formation of AF. Triggered activity is common in all 3 forms of AF, which includes Ca²⁺ handling abnormalities, RyR2-channel dysfunction and triggered activity in form of DADs. Re-entry activity is commonly observed in patients with cAF, but less frequent and consistent in patients with POAF and pAF. The NLRP3 inflammasome is upregulated in all forms of AF, but plays the biggest role as an acute trigger in patients that present with POAF. AP, action potential; APD, action potential duration; cAF, chronic atrial fibrillation; CaMKII, Ca²⁺-calmodulin protein kinase II; DAD, delayed afterdepolarization EAD, early afterdepolarization; JPH-2, junctophilin-2; PKA, protein kinase A; ERP, effective refractory period; NCX, Na⁺/Ca²⁺-exchanger; NLRP3 inflammasome, NACHT, LRR and PYD domains-containing protein 3; pAF, paroxysmal AF; PLB, phospholamban; POAF, post-operative AF; RyR2, ryanodine receptor type-2; SCaE, spontaneous Ca²⁺-release events; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase type-2a; SR, sarcoplasmic reticulum.