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Safe and effective treatment of atrial fibrillation (AF) remains a major unmet medical need in our society, and the problem is growing as the prevalence of AF continues to increase with the aging of the baby boom generation. AF is the most prevalent sustained clinical arrhythmia associated with increased morbidity and mortality. Prevalence of AF is 0.4% to 1% in the general population and greater than 8% among individuals older than 80 years. An estimated 2.5 million individuals in the North America and 4.5 million in Europe are affected by AF.
Atrial Fibrillation and ion channel
New drug development is focused on atrial-selective drugs with the goal of avoiding the ventricular proarrhythmic effects of currently available agents. The normal action potential in atria differs from that of the ventricle with respect to ion channel currents that contribute to resting membrane potential (RMP), phase 1, and phase 3 of the action potential (Figure. 1A and B). Resting membrane potential in atria is more depolarized than in the ventricle due in large part to a smaller inward rectifier potassium current, IK1. Phase 1 is more prominent in atria due to the presence of a prominent transient outward current (Ito) and a current that is exclusive to atria, known as the ultrarapid delayed rectifier potassium current, IKur. The initiation of AF involves the development of both a trigger and a substrate. The electrical substrate develops because of a reduction in wavelength due largely to an abbreviation of effective refractory period (ERP). The maintenance of AF is often facilitated by electrical and structural remodeling which is the result of the rapid activation of the atria. The electrical remodeling further abbreviates ERP by abbreviating the atrial action potential (Figure. 1C). A prolonged period of rapid activation of the atria as occurs during AF leads to a decrease in ICa, IKur, and Ito but to an increase in IK1 and constitutively active IK-ACh. The abbreviation of action potential duration (APD) is due principally to the decrease in ICa and the increase in IK1 and constitutively active IK-ACh.
Figure 1. Differences in ion channel currents of action potentials from normal atria and ventricles and remodeled atria.
Neuronal Nav1.8 Channels
As a tetrodotoxin-resistant periphery nerve voltage-gated sodium channel, Nav1.8 (encoded by SCN10A) plays a significant part in the upstroke of action potential in neurons, and is responsible for repetitive firing. It is found primarily expressed in small- and medium-diameter nociceptive sensory neurons, which mediate pain perception. Genome-wide association study highlights the role of Nav1.8 in cardiac conduction and arrhythmic diseases. In addition to the canonical cardiac sodium channel Nav1.5/SCN5A, Nav1.8 is recently considered a “new cardiac sodium channel.”
Increasing evidence indicates that Nav1.8/SCN10A plays a critical role in AF. Many studies have discovered the intensive relationship between SCN10A variants and AF phenotype or incidence. Besides the significant effect on GP, Nav1.8 might directly influence the electrophysiological characteristics of cardiac tissue with suppressed trigger activity and reduced substrate during AF (Figure 2). The decreased current in INa,P by A-803467 might prolong ERP in atrium by virtue of postrepolarization refractoriness and reduce excitability at the fast rate due to UDB. The prolonged ERP might also prevent the formation of functional substrate during acute AF. Decreased INa,P might also cause conduction block to break the reentrant circuit. Researches indicate that the significantly reduced INa,L seen might suppress the incidence of early after repolarization during AF. A study has reported 17 putative pathogenic SCN10A variants in 25 of 150 Brugada syndrome probands with a positive proband yield of 16.7%. Subsequent studies from others also emphasize the significant of SCN10A in both rare and common variants in Brugada syndrome. Therefore, it can be considered as a novel target in understanding cardiac electrophysiology, and its selective blocker or other relative drug might be promising in SCN10A-related arrhythmias.
Figure 2. Schematic summary of potential pathways of Nav1.8 for regulating cardiac function.
Sodium Channel Block as an Atrial Fibrillation Suppressing Strategy
Na+ channel blockers (NCBs), which block the phase 0 inward sodium current (INa), comprise class I antiarrhythmic agents of the Vaughan-Williams classification. Their main electrophysiological effects are to decrease membrane excitability, decrease conduction velocity in fast-channel tissue, and induce postrepolarization refractoriness. Most clinically available NCBs also have some affinity for the rapid delayed rectifier potassium current (IKr). NCBs are further subdivided into classes IA, IB, and IC, depending on their relative frequency-dependent effects on INa (directly measured or inferred from maximal phase 0 upstroke velocity, Vmax) and action potential duration (APD). Development of an optimized AF-selective NCB has the potential to provide safer and more effective pharmacotherapeutic options for AF, thereby fulfilling a major unmet clinical need.
● Optimized NCB pharmacodynamics
To maximize efficacy and minimize proarrhythmic risk, an NCB should exert strong effects on fibrillating atria and negligible action on ventricular tissue during sinus rhythm, showing “AF selectivity”. AF selectivity may be expressed as the combination of (1) atrial selectivity and (2) rate selectivity. Atrial-selective strategies can target (1) atrial-specific K+ currents, (2) atrial-ventricular differences in Na+ channel properties, and/or (3) atrial-ventricular differences in AP morphology.
● Combining NA+/K+ Channel Blockade
Empirical evidence suggests that ion channel blockers targeting multiple channels, like amiodarone, are safer and more effective than single-channel blockers. Atrial-specific potassium currents (IKur, IK,ACh) circumvent the potentially negative effects of ventricular IKr block and are therefore attractive AF-selective targets. Further work on the role of IKur in healthy and remodeled cardiomyocytes, IKur-specific blockers, and combination therapy may provide new AF-selective options for the rhythm control of AF.
Despite major advances in arrhythmia therapy, AF remains a challenge. A vital limitation in AF management is the lack of safe and effective drugs to restore and maintain sinus rhythm. The rational design of a new generation of AF-selective NCBs is emerging as a promising AF-suppressing strategy. Recent theoretical and experimental advances have generated insights into the mechanisms underlying AF maintenance and termination by anti-arrhythmic drugs. Understanding of anti-arrhythmic drug-induced proarrhythmia has also grown in sophistication. These discoveries have created new possibilities in therapeutic targeting and renewed interest in improved NCB anti-arrhythmic drugs.
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