Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

BACKGROUND: There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). METHODS: The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. RESULTS: Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. CONCLUSIONS: In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

Mild elevation of extracellular potassium greatly potentiates the effect of sodium channel block to cardiovert atrial fibrillation: The Lankenau approach.

BACKGROUND: Cardioversion of atrial fibrillation (AF) is a common clinical necessity, and there is a need for more effective and safe options for acute cardioversion of AF. OBJECTIVE: The purpose of this study was to test the hypothesis that the efficacy and time course of AF cardioversion by sodium channel current (INa) block can be improved by mild elevation of extracellular potassium ([K+]0). METHODS: Using a canine acetylcholine (ACh)-mediated AF model (isolated coronary-perfused right atrial preparations with a rim of right ventricle), we evaluated the ability of flecainide to suppress AF in the presence of [K+]0 ranging from 3 to 8 mM. RESULTS: At [K+]0 of 4 mM (baseline), persistent AF (>1 hour) was induced in 5 of 5 atria in the presence of 0.5 µM ACh. Flecainide alone (1.5 µM) cardioverted 3 of 6 atria at 4 mM [K+]0, 1 of 6 atria at 3 mM [K+]0, 5 of 5 atria at 5 mM and 6 mM [K+]0, and 4 of 4 atria at 8 mM [K+]0. In the absence of flecainide, an increase in [K+]0 from 4 mM to 5, 6, and 8 mM terminated AF in 0 of 5, 2 of 6, and 4 of 4 atria, respectively. The time to conversion was also abbreviated by elevation of [K+]0. After AF termination with flecainide plus elevated [K+]0, AF was either not inducible or brief (<100 seconds). Combined flecainide and elevated [K+]0 (6 mM) caused an atrial preferential depression of excitability. CONCLUSION: Our findings suggest that a combination of INa block accompanied by mild elevation of serum potassium may be a novel approach to more effectively, rapidly, and safely cardiovert AF and prevent its recurrence in the short term.

Advances in basic and translational research in atrial fibrillation.

Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Atrial Fibrillation Induced by Anticancer Drugs and Underling Mechanisms.

ABSTRACT: Cancer therapy has made major progress in the past several decades, but treatments are often accompanied by significant side effects. Arrhythmias are a widespread complication of some antineoplastic drugs, with atrial fibrillation (AF) being the most often encountered drug-associated arrhythmia. Preexisting AF risk factors are commonly present in cancer patients who develop drug-associated AF, and active cancer itself may cause or promote AF. Although anticancer drugs may induce AF in cancer patients without AF risk factors, it appears that most drug-associated AF develop when cancer drugs add or aggravate precancer-existing and/or cancer-related pro-AF factors/alterations, additively or synergistically producing AF. Abnormalities in intracellular calcium activity seem to be involved in the generation of anticancer drug-induced AF. In cancer survivors with cancer therapy-induced cardiomyopathy, AF often occurs, with most of the arrhythmias likely to develop secondary to the cardiomyopathy. AF may lead to modification or even cessation of cancer therapy. The management of AF in patients with cancer is currently conducted largely based on pragmatic assumptions. This review briefly discusses AF caused by anticancer drugs and the underlying mechanisms.

Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Investigational Anti-Atrial Fibrillation Pharmacology and Mechanisms by Which Antiarrhythmics Terminate the Arrhythmia: Where Are We in 2020?

Antiarrhythmic drugs remain the mainstay therapy for patients with atrial fibrillation (AF). A major disadvantage of the currently available anti-AF agents is the risk of induction of ventricular proarrhythmias. Aiming to reduce this risk, several atrial-specific or -selective ion channel block approaches have been introduced for AF suppression, but only the atrial-selective inhibition of the sodium channel has been demonstrated to be valid in both experimental and clinical studies. Among the other pharmacological anti-AF approaches, "upstream therapy" has been prominent but largely disappointing, and pulmonary delivery of anti-AF drugs seems to be promising. Major contradictions exist in the literature about the electrophysiological mechanisms of AF (ie, reentry or focal?) and the mechanisms by which anti-AF drugs terminate AF, making the search for novel anti-AF approaches largely empirical. Drug-induced termination of AF may or may not be associated with prolongation of the atrial effective refractory period. Anti-AF drug research has been largely based on the "suppress reentry" ideology; however, results of the AF mapping studies increasingly indicate that nonreentrant mechanism(s) plays an important role in the maintenance of AF. Also, the analysis of anti-AF drug-induced electrophysiological alterations during AF, conducted in the current study, leans toward the focal source as the prime mechanism of AF maintenance. More effort should be placed on the investigation of pharmacological suppression of the focal mechanisms.

Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes.

BACKGROUND: J wave syndromes (JWS), including Brugada (BrS) and early repolarization syndromes (ERS), are associated with increased risk for life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently very limited. Here, we evaluate the effects of the natural flavone acacetin. METHODS: The effects of acacetin on action potential (AP) morphology and transient outward current (Ito) were first studied in isolated canine RV epicardial myocytes using whole-cell patch clamp techniques. Acacetin's effects on transmembrane APs, unipolar electrograms and transmural ECGs were then studied in isolated coronary-perfused canine RV and LV wedge preparations as well as in whole-heart, Langendorff-perfused preparations from which we recorded a 12 lead ECG and unipolar electrograms. Using floating glass microelectrodes we also recorded transmembrane APs from the RVOT of the whole-heart model. The Ito agonist NS5806, sodium channel blocker ajmaline, calcium channel blocker verapamil or hypothermia (32°C) were used to pharmacologically mimic the genetic defects and conditions associated with JWS, thus eliciting prominent J waves and provoking VT/VF. RESULTS: Acacetin (5-10 µM) reduced Ito density, AP notch and J wave area and totally suppressed the electrocardiographic and arrhythmic manifestation of both BrS and ERS, regardless of the experimental model used. In wedge and whole-heart models of JWS, increasing Ito with NS5806, decreasing INa or ICa (with ajmaline or verapamil) or hypothermia all resulted in accentuation of epicardial AP notch and ECG J waves, resulting in characteristic BrS and ERS phenotypes. Phase 2-reentrant extrasystoles originating from the RVOT triggered VT/VF. The J waves in leads V1 and V2 were never associated with a delay of RVOT activation and always coincided with the appearance of the AP notch recorded from RVOT epicardium. All repolarization defects giving rise to VT/VF in the BrS and ERS models were reversed by acacetin, resulting in total suppression of VT/VF. CONCLUSIONS: We present experimental models of BrS and ERS capable of recapitulating all of the ECG and arrhythmic manifestations of the JWS. Our findings provide definitive support for the repolarization but not the depolarization hypothesis proposed to underlie BrS and point to acacetin as a promising new pharmacologic treatment for JWS.

The Small Conductance Calcium-Activated Potassium Channel Inhibitors NS8593 and UCL1684 Prevent the Development of Atrial Fibrillation Through Atrial-Selective Inhibition of Sodium Channel Activity.

The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.

Is extensive atrial fibrosis in the setting of heart failure associated with a reduced atrial fibrillation burden?

Atrial fibrillation (AF) affects 10-50% of patients with chronic heart failure (HF) and is associated with poor long-term prognosis. AF is commonly associated with atrial structural remodeling (ASR), principally characterized by atrial dilatation and fibrosis. However, the occurrence of AF in the full spectrum of ASR encountered in patients with HF is poorly defined. Experimental studies have presented evidence that extensive ASR can be accompanied with a reduced burden of AF, secondary to a prominent depression of atrial excitability. This reduction in AF burden is associated with severe atrial fibrosis rather than with dilatation. Clinical studies of patients with HF point to the possibility that advanced ASR is associated with a less frequent AF occurrence than moderate ASR. Our goal in this review is to introduce the hypothesis that AF is less likely to occur in severe versus moderate atrial ASR in the setting of HF and that it is severe atrial fibrosis-associated depression of atrial excitability that reduces AF burden.

Late INa Inhibition as an Antiarrhythmic Strategy.

Late sodium channel current (late INa) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late INa is a small current and acceleration of the heart rate decreases late INa density. Late INa influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late INa density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late INa (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late INa and peak INa, and a specific block of late INa might be achieved at slow and normal but seems not at rapid activation rates, at which peak INa, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late INa seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization.

Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis.

INTRODUCTION: Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli. METHODS: Whole cell INa was recorded at room temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug. RESULTS: Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates. CONCLUSION: Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation.

Atria are More Sensitive Than Ventricles to GS-458967-Induced Inhibition of Late Sodium Current.

INTRODUCTION: The differential response of atrial and ventricular cells to late sodium channel current (late INa) inhibition has not been thoroughly investigated. The aim of the present study was to compare the atrioventricular differences in electrophysiological actions of GS-458967, a potent late INa blocker. METHODS AND MATERIALS: Canine coronary-perfused atrial and ventricular preparations and isolated ventricular myocytes were used. Transmembrane action potentials were recorded using standard microelectrode recording techniques. RESULTS: In coronary-perfused preparations paced at a cycle length (CL) of 500 ms, GS-458967 (100-300 nmol/L) significantly abbreviated action potential duration at 50% to 90% (APD50-90) in atria but not in the ventricles. GS-458967 (≥100 nmol/L) prolonged the effective refractory period (ERP) in atria due to the development of postrepolarization refractoriness (PRR) but did not alter ERP in the ventricles. The maximum rate of rise in the action potential upstroke (Vmax) was significantly reduced at concentrations ≥100 nmol/L in atria but not in the ventricles (CL = 300 ms). At slower pacing rates (CL = 2000 ms) and higher concentrations, GS-458967 (100-1000 nmol/L) still failed to abbreviate ventricular APD. However, when APD was prolonged by the rapidly activating delayed rectifier potassium channel blocker E-4031 (1 µmol/L), addition of 1 µmol/L GS-458967 abbreviated APD in the ventricles at slow rates. In contrast, GS-458967 (300 nmol/L) consistently abbreviated APD in untreated isolated ventricular myocytes. CONCLUSION: In canine coronary-perfused preparations, GS-458967 abbreviates APD, induces PRR, and reduces Vmax in atria but has no significant effect on these parameters in the ventricles, indicating an atrial-selective effect of GS-458967 on both peak and late INa-mediated parameters. In multicellular preparations, GS-458967 abbreviated ventricular APD only under long QT conditions, suggesting a pathology-specific action of GS-458967 in canine ventricular myocardium.

Inhibition of IKr potentiates development of atrial-selective INa block leading to effective suppression of atrial fibrillation.

BACKGROUND: The availability of safe and effective drugs for the management of atrial fibrillation (AF) remains an unmet medical need. OBJECTIVES: The purpose of this study was to test the hypothesis that the inhibition of the rapidly activating delayed rectifier potassium current (IKr) greatly potentiates the development of atrial-selective sodium channel current (INa) block, leading to more effective suppression of AF. METHODS: Electrophysiological and anti-AF effects of highly selective INa and IKr blockers (lidocaine and E-4031) individually and in combination were determined in canine coronary-perfused atrial and ventricular preparations. Acetylcholine (1 µM) was used to induce persistent AF. RESULTS: Lidocaine (10 µM) caused a relatively small abbreviation of the action potential duration measured at 90% repolarization in both atria and ventricles, but caused atrial-selective prolongation of the effective refractory period owing to the induction of post-repolarization refractoriness. Lidocaine also caused modest atrial-selective depression of other INa-mediated parameters including excitability, maximum rate of rise of the action potential upstroke, and conduction time. E-4031 (1 µM) prolonged the action potential duration measured at 90% repolarization and effective refractory period in an atrial-predominant manner. A combination of lidocaine and E-4031 caused a greater atrial-selective depression of INa-mediated parameters. Persistent acetylcholine-mediated AF developed in 100% of atria under control conditions, in 80% (4 of 5) after pretreatment with lidocaine (10 µM), in 100% (4 of 4) after E-4031 (1 µM), and in only 14% (1 of 7) after the combination of lidocaine and E-4031. CONCLUSION: Our results provide a proof of concept that IKr block greatly potentiates the effects of rapidly dissociating INa blockers to depress sodium channel-dependent parameters in the canine atria but not in the ventricles, thus contributing significantly to suppression of AF.

Ranolazine effectively suppresses atrial fibrillation in the setting of heart failure.

BACKGROUND: There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF). METHODS AND RESULTS: This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 µmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2-6 weeks at 200-240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current-dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 µmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF. CONCLUSIONS: Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.

A temporal window of vulnerability for development of atrial fibrillation with advancing heart failure.

AIMS: Heart failure (HF) is associated with development of AF and life-threatening ventricular tachycardia and fibrillation (VT/VF). Vulnerability to development of AF and VT/VF at different stages of HF and the underlying pathophysiological mechanisms are poorly defined. The present study was designed to determine the time-course of development of electrical and structural remodelling of the atria and ventricles, and their contribution to induction of AF and VT/VF in a canine model of HF. METHODS AND RESULTS: Dogs were ventricular tachypaced (VTP) for 2-3 weeks or 5-6 weeks ('early' and 'late' HF, respectively). Electrophysiological studies were performed in isolated atrial and ventricular preparations and correlated with cardiac dimensions and haemodynamic parameters recorded in vivo. Vulnerability to programmed electrical stimulation-induced AF was greater in early vs. late stages of HF (78% vs. 38%). In contrast, VT/VF was inducible in late but not in early stages of HF (38% vs. 0%). The temporal distinction in atrial and ventricular arrhythmia susceptibility was associated with a much more rapid development of electrical and structural remodelling in atria. Vulnerability to AF developed following moderate electro-structural remodelling and waned with further progression to severe remodelling, which averted rapid atrial activation. CONCLUSIONS: A temporal window of vulnerability for AF appears relatively early during development of VTP-induced HF in dogs, whereas VT/VF vulnerability is observed at more advanced stages of HF. These findings, if confirmed in humans, may have clinical implications with regard to prognosis and approach to therapy of patients with HF.

Developmental changes in expression and biophysics of ion channels in the canine ventricle.

BACKGROUND: Developmental changes in the electrical characteristics of the ventricular myocardium are not well defined. This study examines the contribution of inwardly rectifying K(+) current (IK1), transient outward K(+) current (Ito), delayed rectifier K(+) currents (IKr and IKs) and sodium channel current (INa) to repolarization in the canine neonate myocardium. METHODS: Single myocytes isolated from the left ventricle of 2-3week old canine neonate hearts were studied using patch-clamp techniques. RESULTS: Neonate cells were ~6-fold smaller than those of adults (28.8±8.8 vs. 176±6.7pF). IK1 was larger in neonate myocytes and displayed a substantial inward component and an outward component with negative slope conductance, peaking at -60mV (4.13 pA/pF). IKr tail currents (at -40mV), were small (<20pA). IKs could not be detected, even after exposure to isoproterenol (100nM). Ito was also absent in the neonate, consistent with the absence of a phase 1 in the action potential. Peak INa, late INa and ICa were smaller in the neonate compared with adults. KCND3, KCNIP2 and KCNQ1 mRNA expression was half, while KCNH2 was equal and KCNJ2 was greater in the neonate when compared with adults. CONCLUSIONS: Two major repolarizing K(+) currents (IKs and Ito) present in adult ventricular cells are absent in the 2week old neonate. Peak and late INa are significantly smaller in the neonate. Our results suggest that the absence of these two currents in the neonate heart may increase the susceptibility to arrhythmias under certain long QT conditions.

Role of late sodium channel current block in the management of atrial fibrillation.

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.