Role of Late Sodium Channel Current Block in the Management of Atrial Fibrillation

Abstract

The anti-arrhythmic efficacy of the late sodium channel current (late I_Na) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late I_Na block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late I_Na and are generally more potent in inhibiting late vs. early I_Na. Selective late I_Na block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late I_Na blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late I_Na in the ventricles, it also potently blocks peak I_Na in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late I_Na inhibition in atria is thought to suppress intracellular calcium (Ca_i)-mediated triggered activity, secondary to a reduction in intracellular sodium (Na_i). However, agents that block late I_Na (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak I_Na blockers, so that the reduction of Na_i loading in atrial cells by these agents can be in large part due to the block of peak I_Na. The impact of late I_Na inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late I_Na block may contribute more to inhibition of Ca_i-mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis.

Introduction

Specific inhibition of late sodium channel current (late I_Na) can effectively suppress ventricular arrhythmias, particularly under conditions of prolonged ventricular repolarization (such as long QT syndrome and heart failure) [1–5]. These anti-arrhythmic actions of selective late I_Na inhibition are largely due to a reduction of intracellular calcium (Ca_i) loading, secondary to a decrease of intracellular sodium (Na_i). Augmented late I_Na may significantly contribute to Na_i loading, which brings calcium into the cell via reverse mode of sodium-calcium exchange. The electrophysiology and pharmacology of late I_Na as well as the antiarrhythmic benefit of its inhibition have been studied mostly in ventricles. The value of block of late I_Na for the suppression of atrial fibrillation (AF) remains poorly investigated. This review examines available data relative to the electrophysiology, pharmacology, and anti-AF ability of late I_Na inhibition.

Electrophysiology of Late Sodium Current

Cardiac sodium channel current is comprised of two basic components: peak and late I_Na. Peak I_Na is responsible for phase 0 of the action potential, whereas late I_Na contributes to the inward charge maintaining phase 2 and phase 3 (Fig. 1). Several mechanism are thought to contribute to the manifestation of late I_Na, including 1) slow inactivation of the sodium channel [6], 2) single as well as bursts of late reopening of the sodium channel [7], and 3) a steady state current occurring within a window of voltage representing the overlap of steady state activation and inactivation of the sodium channel (window current [8]).

Fig. 1.

Role of late I_Na in the action potential (AP) of normal cardiomyocyte. The cardiac AP is comprised of 5 phases (denoted by the numbers). Phase 0, 1, 2, 3, and 4 represent depolarization, early repolarization, “plateau”, late repolarization, and resting state, respectively. Peak I_Na flows into the cell during phase 0 (upstroke of the AP; 1–2 ms duration) and late I_Na during phase 2 and early phase 3 (at potentials positive to –60 mV, peaking at –20 mV; 100–300 ms duration). The density of peak I_Na is significantly greater than that of late I_Na. Action potential duration (APD) is measured at the level of 50–90 % of full repolarization (as depicted by the dashed lines). Specific augmentation of late I_Na (an inward current) prolongs APD and block of this current abbreviates APD

Late I_Na in Ventricular Cells

The amplitude of late I_Na in the ventricles ranges from 0.1 to 1.0 % of that of peak I_Na, depending on species, cell type, pathology, and conditions under which the currents are measured [2, 5]. However, due to a much longer duration during the action potential (100–300 for late I_Na vs. 1–2 ms for peak I_Na), the total charge carried by late I_Na can be considerable. Late I_Na flows into the cell at potentials positive to –60 mV, peaking at –20 mV [9]. Prolongation of action potential duration (APD) increases and abbreviation of APD reduces the integral or total charge of late I_Na.

The relative contribution of late I_Na to Na_i loading increases under pathophysiological conditions associated with an increase in late I_Na density and prolongation of APD (such as heart failure) [2]. Myocardial ischemia in the ventricles is also associated with increased late I_Na density [10]. In contrast, late I_Na has been reported to be reduced in remodeled hypertrophied left ventricles (LV) in a canine chronic AV node block model [4]. It is also noteworthy that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) can increase late I_Na density [11]. There is significant regional heterogeneity in late and peak I_Na density in canine ventricles. Left ventricular midmyocardial to subendocardial M cells have larger late and peak I_Na densities compared to epicardial and endocardial myocytes [9].

Late I_Na in Atrial Cells

Late I_Na is less studied in atrial vs. ventricular cells. The general characteristics of peak and late I_Na appear to be similar in atrial and ventricular cells. However, there are atrioventricular electrophysiological differences that can modulate the relative contribution of late I_Na to Na_i loading. Because APD_50–75 is shorter in atrium vs. ventricle (Fig. 2), the atrial late I_Na integral is likely to be smaller, as is its relative contribution to Na_i loading. While the density of late I_Na is similar in atrial and ventricular cells [12], the density of peak I_Na is significantly greater in atrial vs. ventricular myocytes [13, 14]. However, a more negative steady-state inactivation voltage in atrial vs. ventricular myocytes (~12 mV) [13, 14] as well as a more depolarized resting membrane potential (RMP) in atrial vs. ventricular myocytes reduce the availability of the sodium channel in atria vs. ventricles at the physiologically relevant RMP range. As a result, the range of available peak I_Na appears to be similar in the two chambers as reflected by a similar range of maximum rate of rise of the action potential up-stroke (V_max, an index of peak I_Na) in the canine heart [15, 16]. The exception is Purkinje fiber action potentials, which display the largest peak I_Na and V_max in the heart. The value of V_max generally positively correlates with conduction velocity, i.e., the larger the V_max the faster conduction velocity and vice versa. There is a regional V_max difference in healthy canine right atria (ranging from 356±60 V/s in the endocardial crista terminalis to 234±54 V/s in the epicardial appendage) [15].

Fig. 2.

Action potential duration (APD) is shorter in atria than in. ventricles under baseline conditions and the APD in atrium is significantly abbreviated in remodeled atria (in the setting of atrial fibrillation or prone to develop atrial fibrillation). APD abbreviation reduces the period during which late I_Na flows into the cell, and thus the relative contribution of this current to intracellular sodium (Na_i) loading

Because APD is commonly significantly abbreviated in remodeled atria (Fig. 2), the integral of late I_Na is likely to be smaller in remodeled vs. healthy atria. Properties of atrial late I_Na in AF are poorly studied. The integral of late I_Na (total charge) has been shown to be increased in atrial myocytes isolated from right atrial appendage of persistent AF vs. sinus rhythm patients (by 26 %) [17]. In this study, however, the late I_Na integral in AF and non-AF patients was measured at the same pulse duration, not adjusted to the shorter APD observed in AF. It not known whether late I_Na density is altered in patients with paroxysmal AF. The density of late I_Na in left atria (but not in right atria) has been reported to be increased in a rabbit LV hypertrophy model (caused by hypertension) [18]. Available data relative to alterations of peak I_Na in AF models and patients are controversial. Peak I_Na density in atrial myocytes has been reported to be reduced in persistent AF vs. SR patients in some studies [17] but not others [19]. A decrease in peak I_Na activity was reported in remodeled canine [20], but not goat atria [21]. Interestingly, Na_i was shown to be reduced in canine atrial cells after 48 h of atrial-tachypacing [22].

The magnitude of late I_Na is reverse-rate dependent, i.e., the faster the rate the less the magnitude of this current [9, 23–25]. The rate-dependent reduction of late I_Na contributes to rate-dependent APD abbreviation [9, 25]. The acceleration-induced reduction in late I_Na is much greater than that of peak I_Na (Fig. 3). Thus, the relative contribution of late I_Na in cardiac electrophysiology is thought to be more important when APD is longer and heart rate is slower.

Fig. 3.

Acceleration of heart rate can lead to a reduction in late I_Na total charge in the cardiac cell because of direct rate-dependent reduction in late I_Na density as well as abbreviation of APD. The latter is in part due to the former. Acceleration of pacing rate reduces late I_Na density more than that of peak I_Na [9, 23–25]

Pharmacology of Late Sodium Current

All sodium channel blockers inhibit both peak and late I_Na, typically with a higher potency of blocking late I_Na vs. peak I_Na [26]. Relatively low concentrations of I_Na blockers (including TTX, lidocaine, quinidine, ranolazine, etc) can potently inhibit late I_Na without affecting peak I_Na [1, 26]. Selective pharmacological augmentation of late I_Na prolongs APD/ERP and reduction of this current leads to an abbreviation of APD/ERP (Fig. 1). Block of late I_Na reduces Na_i (and thus Ca_i) and does not directly affect cardiac excitability or conduction properties. Most data dealing with the pharmacology of late I_Na were obtained using ventricular myocytes.

Pharmacology of Late I_Na in Ventricles

The role played by late I_Na is often investigated using ranolazine, currently the most potent late I_Na blocker in ventricles [5]. Ranolazine has been shown to be 9 to 45 times more potent in blocking late vs. peak I_Na in isolated ventricular myocytes and expression systems [5, 27–29]. The study by Udrovinas and colleagues [28] reported an exceptional selectivity of ranolazine to inhibit late vs. peak I_Na in canine ventricular cells (6.5 vs. 294 μM, respectively; i.e., demonstrating an IC₅₀ ratio of 45). Contributing to this high selectivity was the fact that ranolazine's blocking potency was measured at a cycle length (CL) of 10 s, at which the use-dependent effects of the drug are not apparent [14, 30]. Indeed, in canine ventricular myocytes, at slow rates and negative holding potentials (at which all sodium channels are available), 285 μM of ranolazine was needed to cause a 50 % reduction (IC₅₀) of peak I_Na, whereas at faster rates and more “physiological” holding potentials IC₅₀ was less than 10 % of that value [30]. Late I_Na IC₅₀ values for ranolazine inhibition also depend on recording conditions and can range between from 5 to 21 μM in canine ventricular myocytes [24]. Thus, the IC₅₀ of I_Na blockers to inhibit both late and peak I_Na can vary significantly depending on the conditions at which IC₅₀ is measured, including stimulation rate, diastolic interval, holding and test potentials, and temperature [24, 29, 30]. The differences in functional manifestation of late vs. peak I_Na inhibition in multicellular preparations can be even more pronounced, as discussed below.

I_Na blocker-induced inhibition of both peak and late I_Na is rate-dependent (i.e., the faster the rate the greater the blocking efficacy) [12, 24, 26, 29]. The rate-dependence of peak I_Na block is particularly steep for I_Na blockers with rapid unbinding kinetics, such as ranolazine, vernakalant, and amiodarone [14, 26, 30–32]. The rate-dependence of peak vs. late I_Na inhibition is not well investigated. In HEK293 cells expressing a LQT3 mutation (SCN5A-R1623Q), rate-dependent effect of ranolazine to block late and peak I_Na is similar [29]. In cardiac cells, the functional manifestations of rate-dependent peak I_Na block is generally greater than that of late I_Na block (Fig. 4). I_Na blockers with rapid kinetics (e.g., ranolazine and lidocaine) can be highly selective late I_Na blockers at slow heart rates and much less selective or non-selective for late I_Na block at rapid activation rates. Indeed, ranolazine and lidocaine (10–20 μM) significantly abbreviate APD (due to late I_Na block) but have little to no affect on V_max in Purkinje fiber and ventricular M cell preparations at CLs ≥1000 ms [24, 33], thus demonstrating high selectivity for block of late vs. peak I_Na. At rapid rates, these agents significantly reduce V_max with little or no change in APD in ventricular muscles and Purkinje fibers, consistent with much less selective block of late I_Na. Ranolazine (20 μM) causes a 30–40 % reduction of V_max at a CL of 300 ms in canine and human ventricular slice preparations [34]. In canine and human ventricular preparations, ranolazine (10 μM) reduces V_max by 8 and 20 % at a CL of 500 and 300 ms, respectively [14, 34].

Fig. 4.

Effect of acceleration of rate on total charge of atrial peak and late I_Na in the absence and presence of sodium channel blockers with rapid unbinding kinetics. This schema applies only to I_Na blockers that dissociate rapidly from the sodium channel, such as ranolazine, lido-caine, amiodarone (prominent late I_Na blockers). Under baseline conditions, acceleration of pacing rates significantly reduces total charge of late I_Na much more than that of peak I_Na (due to decrease in late I_Na density and APD abbreviation; see Fig. 3). At slow pacing rates and long APDs, block of late I_Na is evidenced by a prominent abbreviation of APD and lack of block of peak I_Na is evidenced by a lack of effect on V_max. At rapid activation rates and relatively short APD, drug-induced block of both late and peak I_Na is augmented. Despite a rate-dependent increase in potency of drug-induced late I_Na block, there is a reduction in absolute amount of total charge of late I_Na blocked following acceleration due to a significant reduction of available pre-drug total charge of late I_Na integral secondary to a reduction of late I_Na density and abbreviation of APD. Due to a much steeper rate-dependent bock of peak I_Na in atria vs. ventricles, the degree of rate-dependent augmentation of peak vs. late I_Na block is likely to be greater in atria vs. ventricles

Pharmacology of Late I_Na in Atria

There are fundamental differences in the response of atria and ventricles to block of peak I_Na. I_Na blockers with relatively rapid unbinding kinetics (like ranolazine amiodarone, vernakalant, AZD1305, Wenxin Keli, etc) are atrial-selective peak I_Na blockers (Figs. 5 and 6). The rate-dependent potency of these agents to inhibit peak I_Na and to depress peak I_Na-mediated parameters (V_max, conduction velocity, excitability, etc) in atrial cells is much greater than in ventricular cells (Figs. 5 and 6) [14, 30, 32, 34–38]. Ranolazine (10 μM), for example, produces little to no change in V_max at a CL of ≥1000 ms in the canine right atrium, but reduces V_max by 25 and 60 % at CLs of 500 and 300 ms, respectively [14, 39]. A major electrophysiological effect of ranolazine, amiodarone, vernakalant, etc (most relevant to their anti-AF action) is the induction atrial-selective post-repolarization refractoriness (PRR), a peak I_Na-mediated parameter (Fig. 5). Our current understanding of the mechanisms of atrial selectivity of I_Na blockers have been discussed in detail elsewhere [39–41] and includes a more depolarized RMP, more negative half-inactivation voltage (V_0.5), and more gradual phase 3 of the action potential in atrial cells as compared with ventricular cells. It is not known whether atrial-selective peak I_Na blockers cause atrial-selective inhibition of late I_Na.

Fig. 5.

Ranolazine selectively induces prolongation of the effective refractory period (ERP) and development of post-repolarization refractoriness in atria (PRR, the difference between ERP and APD₇₅ in atria and between ERP and APD₉₀ in ventricles; ERP corresponds to APD₇₅ in atria and APD₉₀ in ventricles). CL=500 ms. C – control. The arrows in panel A illustrate the position on the action potential corresponding to the end of the ERP in atria and ventricles and the effect of ranolazine to shift the end of the ERP in atria but not ventricles. * p<0.05 vs. control. † = p<0.05 vs. APD₇₅ values in atria and APD₉₀ in ventricles; (n=5–18). From Burashnikov et al. [14], with permission. PRR is a peak I_Na-mediated parameter

Fig. 6.

Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles. a Normalized changes in V_max of atrial and ventricular cardiac preparations paced at a cycle length (CL) of 500 ms. b Ranolazine prolongs late repolarization in atria, but not ventricles and acceleration of rate leads to elimination of the diastolic interval, resulting in a more positive take-off potential in atrium and contributing to atrial selectivity of ranolazine. The diastolic interval remains relatively long in ventricles. * p<0.05 vs. control. † p<0.05 vs. respective values of M cell and Purkinje (n=7–21). From Burashnikov et al. [14], with permission

It is noteworthy that despite the rate-dependence of late I_Na inhibition, the total charge of blocked late I_Na may actually decrease with acceleration of pacing rate due to significant rate-dependent reduction of baseline late I_Na density and abbreviation of APD (Figs. 3 and 4). This suggests that the anti-arrhythmic action of late I_Na block is likely reduced with acceleration of heart rate. Considering the shorter APD in atria vs. ventricles and atrial selectivity of peak I_Na block, I_Na blockers with rapid unbinding kinetics are likely to be less specific late I_Na blockers in atria vs. ventricles, particularly at rapid activation rates.

Pathological conditions often modulate the potency of antiarrhythmic drugs. The efficacy of I_Na blockers to inhibit late I_Na in the setting of AF is poorly defined. The efficacy of ranolazine to inhibit late I_Na is increased and that of peak I_Na is reduced in atrial myocytes isolated from patients with persistent AF [17]. The physiological and anti-AF consequences of these altered blocking efficacies are not clear. However, it is known that I_Na blockers, including ranolazine [42], tend to lose their anti-AF effectiveness in persistent AF patients/models (as discussed in the next section). A reduced ability of ranolazine to block peak I_Na in persistent AF patients is expected to decrease the effectiveness of the drug to induce PRR, thus limiting its anti-AF potency. Selective block of late I_Na is expected to cause a greater APD abbreviation in “healthy” vs. remodeled atria (Fig. 7).

Fig. 7.

Selective late I_Na inhibition produces a greater APD abbreviation in healthy vs. remodeled atrial cells

Anti-Arrhythmic Efficacy of Late Sodium Current Inhibition

The anti-arrhythmic benefit of late I_Na inhibition and the role of late I_Na augmentation in arrhythmogenesis is considerably more studied in ventricles than in atria [5, 43, 44]. Understanding the anti-arrhythmic utility of late I_Na inhibition requires an understanding of the electrophysiological mechanisms underlying the generation of cardiac arrhythmias as well as some atrioventricular differences in arrhythmogeneicity. The occurrence of AF is commonly associated with abbreviation of APD and ERP. In contrast, ventricular tachycardia (VT) and fibrillation (VF) are relatively rarely associated with an abbreviated APD and ERP (i.e., short QT syndrome, acute ischemia, etc.). VT/VF more often occurs under conditions of prolonged APD (heart failure, hypotrophy, long QT syndrome, etc). Sustained electrical remodeling (due to prolonged rapid activation) is associated abbreviation of APD and ERP in atria but prolongation of APD in the ventricles [21, 45].

Tachycardia and fibrillation are normally triggered by a focal source and maintained by a reentrant mechanism [46]. Focal mechanisms include early (EAD) and delayed (DAD) afterdepolarization-induced triggered activity and automaticity [47]. EAD is normally associated with a prolonged APD and bradycardia. An exception is the late phase 3 EAD which requires a significant abbreviation of APD. Phase 3 EAD-induced triggered activity usually develops following an episode of tachycardia followed by a pause [48]. The appearance of DAD is normally associated with tachycardia and relatively short APD. Ca_i overload is a common source of induction of EAD- and DAD-induced triggered activity as well as accelerated automaticity. Reentrant mechanisms are often associated with conduction disturbances and structural and electrical heterogeneities [46]. Most arrhythmic mechanisms are commonly suppressed by APD/ERP prolongation; an exception is bradycardia-mediated EAD activity, which can be inhibited by APD abbreviation [46].

The electrophysiological consequences of late I_Na inhibition (described in the previous sections) suggest that the major anti-arrhythmic value of late I_Na block is in suppression of Ca_i-mediated triggered activity, particularly those occurring in conjunction with APD prolongation and bradycardia.

Ventricular Arrhythmias

Late I_Na has attracted a great deal of attention as an anti-arrhythmic target to suppress ventricular arrhythmias, particularly under conditions of prolonged repolarization, such as those associated with the long QT syndrome, heart failure and bradycardia. These anti-arrhythmic actions of inhibition of late I_Na are due to reduction of repolarization heterogeneity secondary to preferential abbreviation of M cell action potential and suppression of EAD- and DAD-induced triggered activity [5, 24, 49]. EADs associated with a prolongation of repolarization can be suppressed by direct reduction of late I_Na, leading to APD abbreviation (Fig. 8). Abbreviation of APD with late I_Na block may also reduce the total charge carried by the L-type Ca channel current as well, which may contribute to reduction of Ca_i. Because of the presence of a high density of late I_Na in M cells, late I_Na can importantly abbreviate APD in these cells, thus reducing dispersion of repolarization, and suppressing EADs in all long QT types [5, 50].

Fig. 8.

Late I_Na block is effective in suppressing early afterdepolarization-induced triggered activity. The principal mechanisms underlying suppression of early afterdepolarizations by selective late I_Na inhibition include: 1) reduction of inward current and 2) decrease of Na_i and thus Ca_i

Ranolazine has been shown to suppress VF in the setting of myocardial ischemia in pigs in vivo [51, 52]. In addition to its late I_Na inhibition, peak I_Na block by ranolazine may have contributed to this anti-arrhythmic effect of ranolazine, since ERP was significantly prolonged [51]. Ischemia commonly produces depolarization of RMP, which strongly promotes peak I_Na block. Ranolazine (10 μM) effectively suppresses H₂0₂-induced VF in rat [53]. Because H₂0₂ promotes late I_Na, ranolazine's inhibition of late I_Na is likely to importantly contribute to VF suppression. In this study, V_max and conduction velocity were significantly decreased by ranolazine [53], indicating block of peak I_Na.

Atrial Arrhythmias

The therapeutic benefits of peak I_Na block in the setting of AF have long been recognized. The anti-AF action of peak I_Na blockers is due largely to rate-dependent reduction of excitability, prolongation of ERP (secondary to the development of post-repolarization refractoriness), and to conduction block in a critical part of reentrant circuit. Reduction of peak I_Na can also significantly decrease Na_i and, thus, Ca_i, which may suppress Ca_i-mediated triggered activity. There is little information regarding the role of late I_Na in the generation of AF and even less information on potential pharmacological outcomes of the inhibition of this current on AF. In a recent comprehensive review of ranolazine's anti-arrhythmic actions in ventricles and atria, it was concluded that anti-AF ability of ranolazine is largely due to inhibition of peak I_Na and that anti-AF value of late I_Na inhibition appears to be limited to the suppression of trigger(s) under conditions of prolonged atrial repolarization [5].

Clinical and experimental experience indicates that practically all effective anti-AF agents prolong atrial ERP [41, 54]. Potassium channel blockers prolong ERP due to APD prolongation, whereas sodium channel blockers prolong ERP due to induction of rate-dependent post-repolarization refractoriness (PRR); mixed blockers prolong ERP due to both APD prolongation and PRR induction. Because selective late I_Na block does not prolong ERP, reduction of late I_Na alone is unlikely to be significantly effective for the suppression of AF. In fact, inhibition of late I_Na acts to abbreviate APD (Fig. 7 and 8) which may promote AF.

AF is believed to be largely maintained by a reentrant mechanism. Reentrant AF can be suppressed by peak I_Na blockers via reduction of excitability and prolongation of ERP and are unlikely to be significantly affected by selective late I_Na inhibition.

Late I_Na inhibition may however suppress the trigger(s) that initiate AF, particularly under conditions of prolonged APD and bradycardia. Several experimental and clinical studies point to the development of atrial arrhythmias under “atrial” long QT [55–57]. However, clinical experience indicate that repolarization prolonging agents induce proarrhythmias in ventricles but not in atria [58–60], and that only a minority of congenital long QT patients develop AF (<2 %) [61]. Among these patients only one out of 59 LQT3 patients had AF [61]. In another study, 3.2 % of patients with early-onset AF have a SCN5A mutation or rare variant previously associated with long QT3 [62]. Consistent to these clinical data, experimental conditions mimicking LQT1, 2 and 3 and which produce EADs and Torsade de Pointes in canine ventricles [63, 64], do not induce EAD or any arrhythmias in canine atria [65]. It appears that late I_Na inhibition can prevent AF initiation in the “atrial long QT” patients, but the number of patients is likely to be limited.

Apart from long QT syndrome, there are a number of pathological conditions prone to AF which may be associated with a prolongation of atrial APD/ERP and AF occurrence, such as the congestive heart failure [66], atrial dilatation [67, 68] and hypertension [18, 69]. It is noteworthy that in most of these studies [67–69], ERP but not APD was measured and that in many pathological conditions (including heart failure) atrial ERP can prolong without APD prolongation (due to PRR development) [70]. Interestingly, aging, a major pro-AF factor, seems also to be associated with a prolongation of APD and ERP [71, 72]. It is tempting to speculate that prolonged atrial APD in these pathologies and aging is due at least in part to an increase in total charge of late I_Na. Lengthening of APD in atrial myocytes (secondary to an increase in late I_Na) promotes Na_i and then Ca_i loading, leading to the generation of triggered activity and ranolazine has been shown to suppress these activities [73]. Atrial APD is likely to be short in patients experiencing AF or having frequent episodes of AF with any pathology, due to rapid activation-mediated electrical remodeling [21]. Atrial APD can be prolonged in patients who are prone to develop new-onset AF and patients experiencing rare/short episodes of AF, not causing sustained electrical remodeling in atria. In these cases, abbreviation of APD by block of late I_Na may prevent AF initiation.

Tachycardia-mediated triggered activity appears to be less responsive to inhibition of late I_Na compared to bradycardia-mediated triggered activity in atria (Figs. 3 and 4). Ranolazine (10 μM) has been shown to prevent DAD-induced triggered activity (2.0–0.5 Hz) appearing following a period of rapid pacing (5–10 Hz) in superfused canine pulmonary vein (PV) preparations [74]. The primary mechanism of this action of ranolazine appears to be due largely to block of peak I_Na, because ranolazine (10 μM) causes a significant V_max reduction and development of PRR in these PVs [74]. Also, under conditions of a very short APD (APD₈₅<100 ms) and rapid pacing rates (CL0 200–100 ms), ranolazine-induced reduction of Na_i in PV muscular sleeves is likely to be largely due to block of peak I_Na rather than late I_Na. It needs to be recognized that the contribution of late vs. peak I_Na block in the anti-arrhythmic action of ranolazine (or any other I_Na blocker) is difficult to determine. In fact, block of peak I_Na without inhibition of late I_Na is not possible. It is likely that it is a combination of late and peak I_Na inhibition that suppresses the appearance of the Ca_i–mediated triggered activity.

Experimental evidence indicates that ranolazine effectively prevents, terminates, and/or shortens AF only at concentrations that potently inhibit peak I_Na in atria (>5–10 μM), causing a significant rate-dependent depression of excitability and prolongation of PRR [14, 42, 75–77]. Relatively low concentrations of ranolazine (4–5 μM, which are more selective for block of late I_Na but still capable of causing measurable inhibition peak I_Na (Figs. 5 and 6) [14, 75], are less effective against AF [42, 75]. An exception to this rule is AF occurring in the setting of ischemia/reperfusion in atria, where 5 μM ranolazine causes a strong rate-dependent ERP prolongation due to development of PRR and effectively prevents the induction of AF (Fig. 9) [14]. Ranolazine also inhibit late I_Ca current (25–30 % at 2–6 μM [24]) and cause weak block of β-adrenergic receptors [78], which may contribute to its anti-arrhythmic effect. A combination of ranolazine and either dronedarone or amiodarone causes synergistic atrial-selective block of peak I_Na, thus effectively suppressing and preventing the induction of AF in a canine experimental model of AF [75, 79].

Fig. 9.

Ranolazine suppresses AF and/or prevents its induction in two experimental models involving isolated canine arterially-perfused right atria. a Persistent ACh (0.5 μM)-mediated AF is suppressed by ranolazine (10 μM). AF initially converts to flutter and then to sinus rhythm. b ERP measured at a CL of 500 ms is 140 ms. Attempts to re-induce AF fail because ranolazine-induced depression of excitability leads to 1:1 activation failure soon after CL is reduced from 500 to 200 ms (right panel). c Rapid-pacing induces non-sustained AF (48 s duration) following ischemia/reperfusion plus isoproterenol (Iso, 0.2 μmol/L) (left panel). Ranolazine (5 μM) prevents pacing-induced AF due to 1:1 activation failure (right panel). In both models, ranolazine causes prominent use-dependent induction of post-repolarization refractoriness. Reproduced with permission from Burashnikov et al. [14]

The clinical anti-AF efficacy of ranolazine has been demonstrated in several studies. In the MERLIN-TIMI 36 trial, ranolazine treatment was associated with a significant reduction of supraventricular tachyarrhythmias (p<0.001) as well as a 30 % reduction in new onset AF (p=0.08) [80]. Subsequently, a number of small exploratory clinical studies showed the effectiveness of ranolazine to terminate paroxysmal AF [81, 82] and prevent post-operative AF [83]. Ranolazine has been shown also to facilitate electrical cardioversion of AF in cardioversion-resistant patients [84] as well as to improve effectiveness of amiodarone to terminate paroxysmal AF [85].

Apart from ranolazine, there is an abundance of data on the effectiveness of I_Na blockers against AF in both experimental and clinical studies [41, 54, 59], from which the utility of late I_Na inhibition can be deduced. Highly selective I_Na blockers (lidocaine, mexiletine etc, at therapeutically relevant concentrations) are usually not effective against AF, suggesting that reduction of peak and late I_Na (and thus Na_i) alone may be insufficient to effectively terminate and/or prevent AF. In experimental studies, lidocaine suppresses AF only at concentrations causing strong suppression of excitability due to peak I_Na inhibition (clinically toxic concentrations) [14, 86]. Of note, all clinically effective I_Na blockers (including ranolazine) inhibit other currents, particularly I_Kr [40]. In fact, I_Kr block-induced prolongation of atrial repolarization (APD₉₀) greatly synergizes the effect of these agents to depress peak I_Na, at rapid activation rates (Fig. 6) [14, 35, 87].

The anti-AF efficacy of anti-arrhythmic drugs that block I_Na (flecainide, propafenone, amiodarone, etc) is relatively high with paroxysmal AF but low or absent with persistent AF [59]. Available evidence indicates that ranolazine loses its anti-AF efficacy in experimental models of persistent lone AF in the goat [42]. In this respect, the anti-AF value of the increased efficacy of ranolazine to inhibit late I_Na in persistent AF [17] is not clear. A reduced efficacy of ranolazine to block peak I_Na in persistent AF [17] may account for or contribute to the failure of this agent (and perhaps the other I_Na blockers) to terminate persistent AF.

The anti-AF efficacy of ranolazine in specific pathological conditions associated with AF remains poorly studied. It has been reported that ranolazine (5 μM) is effective in preventing AF in canine ischemia/reperfusion-induced AF model [14] as well as AF in canine ventricular tachypacing-induced heart failure model [70]. In both studies, anti-AF efficacy of ranolazine has been largely attributed to block of peak I_Na.

Conclusion

At present there is little specific information regarding the role of late I_Na in the generation of AF and even less information on potential pharmacological outcomes of the specific inhibition of this current on AF. Agents that potently block late I_Na in the ventricles, such as ranolazine and amiodarone, are also atrial-selective peak I_Na blockers and their anti-AF efficacy is due largely to inhibition of peak I_Na. The anti-arrhythmic effectiveness of selective late I_Na inhibition is thought to be greater when APD is long and heart rate is slow. The anti-arrhythmic efficacy of late I_Na block is reduced following acceleration of heart rates and/or abbreviation of APD. Available data suggest that block of late I_Na contributes to prevention of Ca_i-mediated triggered activity capable of initiating AF, particularly in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome)