Ventricular injury in acute left circumflex occlusion: Exploration using precordial bipolar leads and regional vectorcardiograms.

BACKGROUND: Precordial Bipolar Leads (PBLs) provide new electrocardiographic information derived from standard 12­lead ECG recordings. OBJECTIVES: To explore the usefulness of PBLs in patients with acute circumflex coronary artery (CxCA) occlusion. METHODS: Twelve patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were studied before and after acute CxCA occlusion and their data were processed with new methods based on PBLs. RESULTS: The findings were: 1. In right PBL V2-V1, a strong systolic current of injury moving in the left-to-right direction coexists with a strong right-to-left current of injury displayed in left standard unipolar precordial leads (V4, V5 and V6). 2. Ischemic changes lead to a significant increase (approximately 10 ms) in the QRS duration in different leads, although changes in the QRS loop rotation and folding were absent. 3. In the transverse, sagittal, and frontal planes, superimposing two PBLs and the corresponding Regional VCG facilitates the location of the J-point. 4. In the Regional VCGs of this group of patients, J-point and ST segment shifts produced an image that reminds the Greek letter omega (Ω). 5. The currents of injury flowing in opposite directions could result in electrical cancellation that minimizes ECG changes in the standard 12­lead recordings. CONCLUSIONS: Computerized processing of digital, standard 12­lead ECG recordings, provides new valuable diagnostic data in patients with acute CxCA occlusion. The loops revealed important information related to systolic currents of injury. Because these methods use routine 12­lead ECG data, the procedure is based only in software applications. CONDENSED ABSTRACT: Twelve patients undergoing PTCA were studied before and after acute CxCA occlusion and their data were processed with the new methods based on Precordial Bipolar Leads (PBLs) to explore their usefulness. The results showed strong systolic currents of injury in different and sometimes opposite directions in the right-to-left axis and ischemic alterations in the time and amplitude of the QRS waves. The superimposition of two-dimensional coordinates planes (x-y, x-z or z-y) helped to locate the J-point and to display the Regional VCG omega sign (Ω) of myocardial injury. In conclusion, computerized processing of digital ECG data provides new diagnostic information in patients with acute CxCA occlusion.

Right ventricle injury in RCA occlusion: Exploration using precordial bipolar leads and surrogate vectorcardiograms.

BACKGROUND: Precordial Bipolar Leads (PBL) provide new electrocardiographic information derived from standard 12­lead ECG recordings. OBJECTIVES: To explore the usefulness of PBL in patients with acute right coronary artery (RCA) occlusion. METHODS: Sixteen patients undergoing elective percutaneous transluminal coronary angioplasty (PTCA) were studied before and after RCA occlusion and their data were processed with new methods based on PBL. RESULTS: The findings were: 1. In PBL V2-V1, strong systolic currents of injury moving in the left to right direction coexist with those directed towards leads II, III and aVF. 2. Changes in the time of the peaks of the QRS waves do not alter the duration of the QRS. 3. The QRS loops of the surrogate VCG generated show that, during ischemia, the time changes in the peak of the QRS waves displayed in one axis are the consequence of an increase in the amplitude of the waves observed in the perpendicular axis. 4. The use of two simultaneous dimensions (transverse and frontal planes) facilitates the location of the J-point. 5. In the surrogate VCGs of this group of patients, J-point and ST segment shifts produced an image that reminded the Greek letter omega (Ω). 6. The QRS wave changes, in time and amplitude, explained the rotational changes and the ischemic distortions of the surrogate VCG loops. CONCLUSIONS: Computerized processing of ECG data appears to provide new and valuable diagnostic data in patients with acute RCA occlusion. The loops revealed important information related to systolic currents of injury. Because these methods use routine 12­lead ECG data, the procedure is based only in software applications.

J wave syndromes as a cause of malignant cardiac arrhythmias.

The J wave syndromes, including the Brugada (BrS) and early repolarization (ERS) syndromes, are characterized by the manifestation of prominent J waves in the electrocardiogram appearing as an ST segment elevation and the development of life-threatening cardiac arrhythmias. BrS and ERS differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J wave syndromes. Despite over 25 years of intensive research, risk stratification and the approach to therapy of these two inherited cardiac arrhythmia syndromes are still rapidly evolving. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these two syndromes that have captured the interest and attention of the cardiology community over the past two decades.

Acute myocardial ischemia: cellular mechanisms underlying ST segment elevation.

The electrocardiogram (ECG) is an essential tool for the diagnosis of acute myocardial ischemia in the emergency department, as well as for that of an evolving acute myocardial infarction (AMI). Changes in the surface ECG in leads whose positive poles face the ischemic region are known to be related to injury currents flowing across the boundaries between the ischemic and the surrounding normal myocardium. Although experimental studies have also shown an endocardium to epicardium differential sensitivity to the effect of acute ischemia, the important contribution of this transmural heterogeneous response to the changes observed in the surface ECG is less appreciated by the clinical cardiologist. This review briefly discusses our current knowledge regarding the electrophysiology of the ischemic myocardium focusing primarily on the electrophysiologic changes underlying the ECG alterations observed at the onset of a transmural AMI.

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.

Optical and electrical recordings from isolated coronary-perfused ventricular wedge preparations.

The electrophysiological heterogeneity that exists across the ventricular wall in the mammalian heart has long been recognized, but remains an area that is incompletely understood. Experimental studies of the mechanisms of arrhythmogenesis in the whole heart often examine the epicardial surface in isolation and thereby disregard transmural electrophysiology. Significant heterogeneity exists in the electrophysiological properties of cardiomyocytes isolated from different layers of the ventricular wall, and given that regional heterogeneities of membrane repolarization properties can influence the electrophysiological substrate for re-entry, the diversity of cell types and characteristics spanning the ventricular wall is important in the study of arrhythmogenesis. For these reasons, coronary-perfused left ventricular wedge preparations have been developed to permit the study of transmural electrophysiology in the intact ventricle. Since the first report by Yan and Antzelevitch in 1996, electrical recordings from the transmural surface of canine wedge preparations have provided a wealth of data regarding the cellular basis for the electrocardiogram, the role of transmural heterogeneity in arrhythmogenesis, and differences in the response of the different ventricular layers to drugs and neurohormones. Use of the wedge preparation has since been expanded to other species and more recently it has also been widely used in optical mapping studies. The isolated perfused wedge preparation has become an important tool in cardiac electrophysiology. In this review, we detail the methodology involved in recording both electrical and optical signals from the coronary-perfused wedge preparation and review the advances in cardiac electrophysiology achieved through study of the wedge.

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.

Identification and characterization of a transient outward K+ current in human induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: The ability to recapitulate mature adult phenotypes is critical to the development of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) as models of disease. The present study examines the characteristics of the transient outward current (Ito) and its contribution to the hiPSC-CM action potential (AP). METHOD: Embryoid bodies were made from a hiPS cell line reprogrammed with Oct4, Nanog, Lin28 and Sox2. Sharp microelectrodes were used to record APs from beating-clusters (BC) and patch-clamp techniques were used to record Ito in single hiPSC-CM. mRNA levels of Kv1.4, KChIP2 and Kv4.3 were quantified from BCs. RESULTS: BCs exhibited spontaneous beating (60.5±2.6 bpm) and maximum-diastolic-potential (MDP) of 67.8±0.8 mV (n=155). A small 4-aminopyridine-sensitive phase-1-repolarization was observed in only 6/155 BCs. A robust Ito was recorded in the majority of cells (13.7±1.9 pA/pF at +40 mV; n=14). Recovery of Ito from inactivation (at -80 mV) showed slow kinetics (τ1=200±110 ms (12%) and τ2=2380±240 ms (80%)) accounting for its minimal contribution to the AP. Transcript data revealed relatively high expression of Kv1.4 and low expression of KChIP2 compared to human native ventricular tissues. Mathematical modeling predicted that restoration of IK1 to normal levels would result in a more negative MDP and a prominent phase-1-repolarization. CONCLUSION: The slow recovery kinetics of Ito coupled with a depolarized MDP account for the lack of an AP notch in the majority of hiPSC-CM. These characteristics reveal a deficiency for the development of in vitro models of inherited cardiac arrhythmia syndromes in which Ito-induced AP notch is central to the disease phenotype.

Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia.

BACKGROUND: Brugada (BrS) and early repolarization syndromes (ERS), the so-called J wave syndromes (JWS), are associated with life-threatening ventricular arrhythmias. Pharmacologic approaches to therapy are currently limited. In this study, we examine the effects of ARumenamide-787 (AR-787) to suppress the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. METHODS: We studied the effects of AR-787 on INa and IKr in HEK-293 cells stably expressing the α- and ß1-subunits of the cardiac (NaV1.5) sodium channel and hERG channel, respectively. In addition, we studied its effect on Ito, INa and ICa in dissociated canine ventricular myocytes along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The Ito agonist, NS5806 (5-10 µM), ICa blocker, verapamil (2.5 µM), and INa blocker, ajmaline (2.5 µM), were used to mimic the genetic defects associated with JWS and to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry and polymorphic VT/VF) in canine ventricular wedge preparations. RESULTS: AR-787 (1, 10 and 50 µM) exerted pleiotropic effects on cardiac ion channels. The predominant effect was inhibition of the transient outward current (Ito) and enhancement of the sodium channel current (INa), with lesser effects to inhibit IKr and augment calcium channel current (ICa). AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. CONCLUSIONS: Our findings point to AR-787 as promising candidate for the pharmacologic treatment of JWS and hypothermia.

Physiological consequences of transient outward K+ current activation during heart failure in the canine left ventricle.

BACKGROUND: Remodeling of ion channel expression is well established in heart failure (HF). We determined the extent to which I(to) is reduced in tachypacing-induced HF and assessed the ability of an I(to) activator (NS5806) to recover this current. METHOD AND RESULTS: Whole-cell patch clamp was used to record I(to) in epicardial (Epi) ventricular myocytes. Epi- and endocardial action potentials were recorded from left ventricular wedge preparations. Right ventricular tachypacing-induced heart failure reduced I(to) density in Epi myocytes (Control=22.1±1.9pA/pF vs 16.1±1.4 after 2weeks and 10.7±1.4pA/pF after 5 weeks, +50mV). Current decay as well as recovery of I(to) from inactivation progressively slowed with the development of heart failure. Reduction of I(to) density was paralleled by a reduction in phase 1 magnitude, epicardial action potential notch and J wave amplitude recorded from coronary-perfused left ventricular wedge preparations. NS5806 increased I(to) (at +50mV) from 16.1±1.4 to 23.9±2.1pA/pF (p<0.05) at 2weeks and from 10.7±1.4 to 14.4±1.9pA/pF (p<0.05) in 5 weeks tachypaced dogs. NS5806 increased both fast and slow phases of I(to) recovery in 2 and 5-week HF cells and restored the action potential notch and J wave in wedge preparations from HF dogs. CONCLUSIONS: The I(to) agonist NS5806 increases the rate of recovery and density of I(to), thus reversing the HF-induced reduction in these parameters. In wedge preparations from HF dogs, NS5806 restored the spike-and-dome morphology of the Epi action potential providing proof of principal that some aspects of electrical remodelling during HF can be pharmacologically reversed.

Ionic and cellular mechanisms underlying the development of acquired Brugada syndrome in patients treated with antidepressants.

INTRODUCTION: Tricyclic antidepressants are known to induce cardiac arrhythmias at therapeutic or supratherapeutic doses. The tricyclic antidepressant, amitriptyline, is reported to induce ST segment elevation in the right precordial electrocardiogram (ECG) leads, thus unmasking Brugada syndrome (BrS). The mechanism by which antidepressants induce the BrS phenotype and associated sudden death is not well established. METHODS AND RESULTS: Action potentials (AP) were simultaneously recorded from epicardial and endocardial sites of isolated coronary-perfused canine right ventricular wedge preparations, together with a transmural pseudo-ECG. Amitriptyline alone (0.2 µM-1 mM) failed to induce a BrS phenotype. NS5806 (8 µM), a transient outward potassium channel current (I(to) ) agonist, was used to produce an outward shift of current mimicking a genetic predisposition to BrS. In the presence of NS5806, a therapeutic concentration of amitriptyline (0.2 µM) accentuated the epicardial AP notch leading to ST-segment elevation of the ECG. All-or-none repolarization at some epicardial sites but not others gave rise to phase-2-reentry and polymorphic ventricular tachycardia (VT) in 6 of 9 preparations. Isoproterenol (100 nM) or quinidine (10 µM) reversed the effects of amitriptyline aborting phase 2 reentry and VT (4/4). Using voltage-clamp techniques applied to isolated canine ventricular myocytes, 0.2 µM amitriptyline was shown to produce use-dependent inhibition of sodium channel current (I(Na) ), without significantly affecting I(to) (n = 5). CONCLUSIONS: Our data suggest that amitriptyline-induced inhibition of I(Na) unmasks the Brugada ECG phenotype and facilitates development of an arrhythmogenic substrate only in the setting of a genetic predisposition by creating repolarization heterogeneities that give rise to phase 2 reentry and VT.

J wave syndromes: What's new?

Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J wave syndromes, which include the Brugada (BrS) and early repolarization (ERS) syndromes. These ion channelopathies are responsible for sudden cardiac death (SCD), most often in young adults in the third and fourth decade of life. Our principal goal in this review is to briefly outline the clinical characteristics, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these primary electrical diseases that have challenged the cardiology community over the past two decades. In addition, we discuss our recently developed whole-heart experimental model of BrS, providing compelling evidence in support of the repolarization hypothesis for the BrS phenotype as well as novel findings demonstrating that voltage-gated sodium and transient outward current channels can modulate each other's function via trafficking and gating mechanisms with implications for improved understanding of the genetics of both cardiac and neuronal syndromes.

Extracellular proton depression of peak and late Na⁺ current in the canine left ventricle.

Cardiac ischemia reduces excitability in ventricular tissue. Acidosis (one component of ischemia) affects a number of ion currents. We examined the effects of extracellular acidosis (pH 6.6) on peak and late Na(+) current (I(Na)) in canine ventricular cells. Epicardial and endocardial myocytes were isolated, and patch-clamp techniques were used to record I(Na). Action potential recordings from left ventricular wedges exposed to acidic Tyrode solution showed a widening of the QRS complex, indicating slowing of transmural conduction. In myocytes, exposure to acidic conditions resulted in a 17.3 ± 0.9% reduction in upstroke velocity. Analysis of fast I(Na) showed that current density was similar in epicardial and endocardial cells at normal pH (68.1 ± 7.0 vs. 63.2 ± 7.1 pA/pF, respectively). Extracellular acidosis reduced the fast I(Na) magnitude by 22.7% in epicardial cells and 23.1% in endocardial cells. In addition, a significant slowing of the decay (time constant) of fast I(Na) was observed at pH 6.6. Acidosis did not affect steady-state inactivation of I(Na) or recovery from inactivation. Analysis of late I(Na) during a 500-ms pulse showed that the acidosis significantly reduced late I(Na) at 250 and 500 ms into the pulse. Using action potential clamp techniques, application of an epicardial waveform resulted in a larger late I(Na) compared with when an endocardial waveform was applied to the same cell. Acidosis caused a greater decrease in late I(Na) when an epicardial waveform was applied. These results suggest acidosis reduces both peak and late I(Na) in both cell types and contributes to the depression in cardiac excitability observed under ischemic conditions.

Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes.

INTRODUCTION: NS5806 activates the transient outward potassium current (I(to) ) in canine ventricular cells. We compared the effects of NS5806 on canine atrial versus ventricular tissues and myocytes. METHODS AND RESULTS: NS5806 (10 µM) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 µM) accentuated phase 1 in epicardium (Epi), with little effect in endocardium (Endo), resulting in augmented J-waves on the ECG. In contrast, application of NS5806 (10 µM) to atrial preparations had no effect on phase 1 repolarization but significantly decreased upstroke velocity (dV/dt) and depressed excitability, consistent with sodium channel block. Current and voltage-clamp recordings were made in the absence and presence of NS5806 in (10 µM) enzymatically dissociated atrial and ventricular myocytes. In ventricular myocytes, NS5806 increased I(to) magnitude by 80% and 16% in Epi and Endo, respectively (at +40 mV). In atrial myocytes, NS5806 increased peak I(to) by 25% and had no effect on the sustained current, I(Kur) . Under control conditions, I(Na) density in atrial myocytes was nearly double that in ventricular myocytes. NS5806 caused a shift in steady-state mid-inactivation (V(1/2)) from -73.9 ± 0.27 to -77.3 ± 0.21 mV in ventricular and from -82.6 ± 0.12 to -85.1 ± 0.11 mV in atrial cells, resulting in reduction of I(Na) in both cell types. Expression of mRNA encoding putative I(Na) and I(to) channel subunits was evaluated by qPCR. CONCLUSION: NS5806 produces a prominent augmentation of I(to) with little effect on I(Na) in the ventricles, but a potent inhibition of I(Na) with little augmentation of I(to) in atria.

The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization.

This Point/Counterpoint presents a scholarly debate of the mechanisms underlying the electrocardiographic and arrhythmic manifestations of Brugada syndrome (BrS), exploring in detail the available evidence in support of the repolarization vs. depolarization hypothesis.

AZD1305 exerts atrial predominant electrophysiological actions and is effective in suppressing atrial fibrillation and preventing its reinduction in the dog.

Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrial selective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, canine isolated arterially perfused preparations in vitro, and isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential upstroke (V(max)) predominantly in atria (-51% +/- 10% in atria vs. -31% +/- 23% in ventricles; 3 microM; cycle length = 500 milliseconds). Fast sodium current (I(Na)) was blocked by AZD1305 to a greater degree in atrial versus ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5 of 5 and 7 of 8 atria, respectively). In conclusion, AZD1305 exerts atrial predominant sodium channel-blocking effects in vitro and in vivo and effectively suppresses AF.

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.

Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine.

BACKGROUND: The development of selective atrial antiarrhythmic agents is a current strategy for suppression of atrial fibrillation (AF). METHODS AND RESULTS: Whole-cell patch clamp techniques were used to evaluate inactivation of peak sodium channel current (I(Na)) in myocytes isolated from canine atria and ventricles. The electrophysiological effects of therapeutic concentrations of ranolazine (1 to 10 micromol/L) and lidocaine (2.1 to 21 micromol/L) were evaluated in canine isolated coronary-perfused atrial and ventricular preparations. Half-inactivation voltage of I(Na) was approximately 15 mV more negative in atrial versus ventricular cells under control conditions; this difference increased after exposure to ranolazine. Ranolazine produced a marked use-dependent depression of sodium channel parameters, including the maximum rate of rise of the action potential upstroke, conduction velocity, and diastolic threshold of excitation, and induced postrepolarization refractoriness in atria but not in ventricles. Lidocaine also preferentially suppressed these parameters in atria versus ventricles, but to a much lesser extent than ranolazine. Ranolazine produced a prolongation of action potential duration (APD90) in atria, no effect on APD90 in ventricular myocardium, and an abbreviation of APD90 in Purkinje fibers. Lidocaine abbreviated both atrial and ventricular APD90. Ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF. CONCLUSIONS: Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.