TY - JOUR
T1 - Emerging Antiarrhythmic Drugs for Atrial Fibrillation
AU - Saljic, A.
AU - Heijman, J.
AU - Dobrev, D.
N1 - Funding Information:
Funding: This work for supported by funding from the Independent Research Fund Denmark (102900011B to A.S.), the Netherlands Organization for Scientific Research (NWO/ZonMW Vidi 09150171910029 to J.H.), the National Institutes of Health (R01HL136389, R01HL131517 and R01HL089598 to D.D.), the German Research Foundation (DFG, Do 769/4-1 to D.D.), and the European Union (large-scale integrative project MEASTRIA, No. 965286 to D.D.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/4/1
Y1 - 2022/4/1
N2 - 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.
AB - 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.
KW - atrial fibrillation
KW - pharmacology
KW - ectopic activity
KW - fibroblast
KW - POLYMORPHIC VENTRICULAR-TACHYCARDIA
KW - ACTIVATED POTASSIUM CHANNELS
KW - CA2+-ACTIVATED K+ CHANNELS
KW - CHRONIC HEART-FAILURE
KW - RYANODINE RECEPTOR
KW - CALCIUM-RELEASE
KW - MOLECULAR DETERMINANTS
KW - SARCOPLASMIC-RETICULUM
KW - CARDIAC FIBROBLASTS
KW - CA2+ LEAK
U2 - 10.3390/ijms23084096
DO - 10.3390/ijms23084096
M3 - (Systematic) Review article
C2 - 35456912
SN - 1661-6596
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 8
M1 - 4096
ER -