Molecular Basis of Atrial Fibrillation Pathophysiology and Therapy

Abstract

Atrial fibrillation (AF) is a highly prevalent arrhythmia, with substantial associated morbidity and mortality. There have been significant management advances over the past 2 decades, but the burden of the disease continues to increase and there is certainly plenty of room for improvement in treatment options. A potential key to therapeutic innovation is a better understanding of underlying fundamental mechanisms. This article reviews recent advances in understanding the molecular basis for AF, with a particular emphasis on relating these new insights to opportunities for clinical translation. We first review the evidence relating basic electrophysiological mechanisms to the characteristics of clinical AF. We then discuss the molecular control of factors leading to some of the principal determinants, including abnormalities in impulse conduction (such as tissue fibrosis and other extra-cardiomyocyte alterations, connexin dysregulation and Na + -channel dysfunction), electrical refractoriness, and impulse generation. We then consider the molecular drivers of AF progression, including a range of Ca 2+ -dependent intracellular processes, microRNA changes, and inflammatory signaling. The concept of key interactome-related nodal points is then evaluated, dealing with systems like those associated with CaMKII (Ca 2+ /calmodulin-dependent protein kinase-II), NLRP3 (NACHT, LRR, and PYD domains-containing protein-3), and transcription-factors like TBX5 and PitX2c. We conclude with a critical discussion of therapeutic implications, knowledge gaps and future directions, dealing with such aspects as drug repurposing, biologicals, multispecific drugs, the targeting of cardiomyocyte inflammatory signaling and potential considerations in intervening at the level of interactomes and gene-regulation. The area of molecular intervention for AF management presents exciting new opportunities, along with substantial challenges.

COVID-19 associated atrial fibrillation: Incidence, putative mechanisms and potential clinical implications

“…Arrhythmias are frequently reported in COVID-19 patients, with atrial fibrillation (AF) being the most common form. Although electrical, calcium handling, and structural remodeling plays a key role in AF pathophysiology [6] , [7] , [8] , [9] , the clinical presentation of AF is diverse and the precise mechanisms of AF remain unclear in a large proportion of patients [10] . The underlying causes of AF in COVID-19 patients are largely unknown.…”

Molecular Targets and Pathways Contributing to the Effects of Wenxin Keli on Atrial Fibrillation Based on a Network Pharmacology Approach

“…The targets were closely related to membrane raft extracellular matrix, RNA polymerase II transcription factor complex, endoplasmic reticulum lumen, neuron projection cytoplasm, mitochondrial outer membrane, perinuclear region of cytoplasm, focal adhesion, and nuclear membrane. Previous study showed interconnectivity of numerous targets functioning in the cardiomyocyte cell membrane, sarcoplasmic reticulum, nucleus, sarcomere, and inflammasome with reported roles in human or preclinical models of AF [ 31 , 32 ]. Thus, it can be seen that WXKL plays a role in the treatment of AF through these cell components category.…”

Personalization of mathematical models of human atrial action potential

“…Long-term persistent AF is associated with extensive atrial remodeling and, in particular, with changes in ionic channels conductivities [19]. These changes shorten the APD [7][8][9][10]20], causing a decrease in effective reentrant wavelength, which affects the sustainability of arrhythmia [21].…”