Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia, largely associated to morbidity and mortality. Over the past decades, research in appearance and progression of this arrhythmia have turned into significant advances in its management. However, the incidence of AF continues to increase with the aging of the population and many important fundamental and translational underlaying mechanisms remain elusive. Here, we review recent advances in molecular and cellular basis for AF initiation, maintenance and progression. We first provide an overview of the basic molecular and electrophysiological mechanisms that lead and characterize AF. Next, we discuss the upstream regulatory factors conducting the underlying mechanisms which drive electrical and structural AF-associated remodeling, including genetic factors (risk variants associated to AF as transcriptional regulators and genetic changes associated to AF), neurohormonal regulation (i.e., cAMP) and oxidative stress imbalance (cGMP and mitochondrial dysfunction). Finally, we discuss the potential therapeutic implications of those findings, the knowledge gaps and consider future approaches to improve clinical management.
Highlights
Atrial fibrillation (AF) is a growing epidemic associated to increased morbidity and mortality [1]
Multiple potential mediators have been described to cause pathologic changes leading to the atrial substrate and electrical remodeling associated to AF (Figure 2), including hereditable genes, inflammation, fibrosis, oxidative stress, pressure and/or volume overload and autonomic changes
Regulated Ca2+ -handling microdomains include Na+ /Ca2+ exchanger (NCX) and L-type Ca2+ channel (LTCC) at the cell membrane, ryanodine receptor (RyR) and sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), which is inhibited by sarcolipin (SLP) and phospholamban (PLB), at the sarcoplasmic reticulum (SR) membrane, the NOD, LRR- and pyrin domain-containing protein 3 (NLRP3), and contractile proteins at the myofilaments
Summary
Atrial fibrillation (AF) is a growing epidemic associated to increased morbidity and mortality [1]. Medium/long-term sinus rhythm maintenance after cardioversion or ablation of AF is not yet possible, and the progressive nature of AF is limiting the long-term success of current management therapies [3]. For AF to initiate and develop into a maintenance state, it requires a trigger and a vulnerable substrate [4]. This review highlights the recent advances in understanding the potential mediators and the molecular basis underlying initiation, maintenance and progression of AF, as well as highlighting resulting therapeutical implications and knowledge gaps. A number of pathophysiological mechanisms have been proposed to underly initiation and maintenance of AF (Figure 1).
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