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Objectives: We tested proposed algorithms for idiopathic and nonischemic tachycardias for their ability to identify epicardial LV-VT origins., Background: Several ECG features have been reported to identify epicardial origins for left ventricular tachycardias (LV-VTs) in the absence of myocardial infarction. Only limited data exist in postinfarction patients., Methods: The QRS features of 24 VTs that were ablated from the epicardium and 39 left ventricular VTs ablated from the endocardium were retrospectively analyzed for various 12-lead ECG features previously reported., Results: No ECG feature consistently predicted an epicardial LV-VT origin in infarct-related tachycardias, with epicardial VTs showing slightly longer QRS durations (189 ± 32 ms in epicardial vs 179 ± 37 ms in endocardial, P = 0.28). Pseudo-delta duration was 38 ± 27 versus 47 ± 27 ms (P = 0.2), intrinsicoid deflection time 93 ± 35 versus 86 ± 32 ms (P = 0.4), shortest RS 97 ± 38 versus 99 ± 32 ms (P = 0.77), and median deflection index 0.82 ± 0.25 versus 0.87 ± 0.22 (P = 0.43). The finding of a Q wave in lead I and the absence of a Q wave in the inferior leads failed to predict an epicardial origin in superior LV-VT sites. Q waves in any inferior lead and aVR/aVL-ratio<1 were not specific for an epicardial origin in inferior sites (all P = ns). Furthermore, all inferior LV-VTs showed a Q wave in the inferior leads which correlated with pre-existing Q-waves in sinus rhythm (P = 0.045)., Conclusion: Proposed 12-lead ECG features for differentiation of epicardial versus endocardial sites for nonischemic LV-VTs do not reliably identify VTs that require ablation from the epicardium. Endocardial mapping should be the first approach to catheter ablation for VTs in patients with ischemic heart disease., (© 2011 Wiley Periodicals, Inc.)

Introduction: Mechanical stimulation can induce electrophysiologic changes in cardiac myocytes, but how mechanoelectric feedback in the intact heart affects action potential propagation remains unclear., Methods and Results: Changes in action potential propagation and repolarization with increased left ventricular end-diastolic pressure from 0 to 30 mmHg were investigated using optical mapping in isolated perfused rabbit hearts. With respect to 0 mmHg, epicardial strain at 30 mmHg in the anterior left ventricle averaged 0.040 +/- 0.004 in the muscle fiber direction and 0.032 +/- 0.006 in the cross-fiber direction. An increase in ventricular loading increased average epicardial activation time by 25%+/- 3% (P < 0.0001) and correspondingly decreased average apparent surface conduction velocity by 16%+/- 7% (P = 0.007). Ventricular loading did not significantly alter action potential duration at 20% repolarization (APD20) but did at 80% repolarization (APD80), from 179 +/- 7 msec to 207 +/- 5 msec (P < 0.0001). The dispersion of APD20 was decreased with loading from 19 +/- 2 msec to 13 +/- 2 msec (P = 0.024), whereas the dispersion of APD80 was not significantly changed. These electrophysiologic changes with ventricular loading were not affected by the nonspecific stretch-activated channel blocker streptomycin (200 microM) and were not attributable to changes in myocardial perfusion or the presence of an electromechanical decoupling agent (butanedione monoxime) during optical mapping., Conclusion: Acute loading of the left ventricle of the isolated rabbit heart decreased apparent epicardial conduction velocity and increased action potential duration by a load-dependent mechanism that may not involve stretch-activated channels.

Introduction: Increased vagal tone significantly enhances susceptibility to atrial fibrillation (AF); however, the cellular mechanisms responsible for vagally mediated AF are not completely understood., Methods and Results: In 12 isolated arterially perfused canine right atria, high-resolution optical mapping techniques were used to measure action potentials during control conditions, during intracardiac parasympathetic nerve stimulation (IPS; 30 to 50 Hz) as a surrogate for vagal stimulation, and during acetylcholine (ACh) infusion (10 to 30 microM). During steady-state pacing, action potential duration was shorter during ACh infusion (43 +/- 9 msec) than during IPS (78 +/- 7 msec, P < 0.001) or control (129 +/- 5 msec, P < 0.001). In contrast, repolarization gradients were larger during IPS (13 +/- 3 msec/mm) than during ACh infusion (3 +/- 1 msec/mm, P < 0.01) or control (5 +/- 1 msec/mm, P < 0.01). Transmural repolarization gradients were relatively small for each intervention tested. During ACh infusion, atrial tachyarrhythmia (AT) was easily initiated with a single premature stimulus and was associated with a focal pattern of activation (84%). AT also was easily initiated by a single premature stimulus during IPS; however, when repolarization gradients were large, patterns of conduction block and incomplete macroreentry were often observed (64%). Importantly, AT initiation during IPS was associated with focal activity (36%) when repolarization gradients were small., Conclusion: In contrast to ACh infusion, IPS generally increased dispersion of repolarization and was often associated with patterns of conduction block and incomplete macroreentry, similar to that associated with in vivo cervical vagal stimulation. However, IPS also was associated with a focal pattern of initiation that was independent of local repolarization gradients. These results suggest that during vagal stimulation, AT initiation does not always depend on repolarization gradients.

Introduction: We hypothesized that in humans there is an epicardial fat pad from which parasympathetic ganglia supply the AV node. We also hypothesized that the parasympathetic nerves innervating the AV node also innervate the right atrium, and the greatest density of innervation is near the AV nodal fat pad., Methods and Results: An epicardial fat pad near the junction of the left atrium and right inferior pulmonary vein was identified during cardiac surgery in seven patients. A ring electrode was used to stimulate this fat pad intraoperatively during sinus rhythm to produce transient complete heart block. Subsequently, temporary epicardial wire electrodes were sutured in pairs on this epicardial fat pad, the high right atrium, and the right ventricle by direct visualization during coronary artery bypass surgery in seven patients. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness at each catheter site was determined in the presence and absence of parasympathetic nerve stimulation (via the epicardial wires). In all seven patients, an AV nodal fat pad was identified. Fat pad stimulation during and after surgery caused complete heart block but no change in sinus rate. Fat pad stimulation decreased the right atrial effective refractory period at 1 cm (280 +/- 42 msec to 242 +/- 39 msec) and 2 cm (235 +/- 21 msec to 201 +/- 11 msec) from the fat pad (P = 0.04, compared with baseline). No significant change in atrial refractoriness occurred at distances >2 cm. The response to stimulation decreased as the distance from the fat pad increased., Conclusion: For the first time in humans, an epicardial fat pad was identified from which parasympathetic nerve fibers selectively innervate the AV node but not the sinoatrial node. Nerves in this fat pad also innervate the surrounding right atrium.

Introduction: Procainamide delivery into the pericardial space may produce a greater and more prolonged electrophysiologic effect, particularly in thin superficial atrial tissue, compared with intravenous delivery., Methods and Results: Swine were randomized to sequential procainamide doses delivered intravenously (n = 6) or into the pericardial space (n = 7). The cumulative pericardial doses were 0.5, 1.5, and 3.5 mg/kg, and the intravenous doses were 2, 10, and 26 mg/kg. Pericardial procainamide prolonged right atrial effective refractory period from baseline by 22% (P < 0.01) but only at the 3.5 mg/kg cumulative dose. This dose slowed interatrial conduction time by 14% (P < 0.05) and raised atrial fibrillation threshold by 70 mA (P < 0.05). Pericardial procainamide had minimal effect on ventricular electrophysiology. Similar results occurred with a single 2 mg/kg pericardial dose in a closed chest model. Intravenous 10 and 26 mg/kg cumulative doses prolonged atrial effective refractory period from baseline by 24% and 18% (P < 0.01), respectively. The 26 mg/kg cumulative intravenous dose slowed interatrial and atrial-ventricular conduction times by 27% and 17%, respectively (P < 0.05), raised atrial fibrillation threshold, and slowed ventricular conduction time by 29% (P < 0.05). Pericardial procainamide produced pericardial fluid concentrations ranging from 250 to 1,500 microg/mL, but plasma concentrations were <1 microg/mL. Intravenous procainamide doses produced pericardial fluid concentrations similar to plasma trough concentrations 0 to 12 microg/mL., Conclusion: The single 2 mg/kg and 3.5 mg/kg cumulative pericardial procainamide doses prolonged atrial refractoriness and raised atrial fibrillation threshold similar to the 26 mg/kg cumulative intravenous dose, but the duration of effect was similar between delivery methods. Pericardial procainamide did not affect global or endocardial ventricular electrophysiology nor was it associated with ventricular proarrhythmia.

Introduction: Previous studies from our laboratory demonstrated (1) a much larger I(Ks) and (2) inability to induce early afterdepolarization (EAD) activity in epicardial and endocardial cells versus M cells. This study tests the hypothesis that these two characteristics are interrelated., Methods and Results: Standard and floating microelectrode techniques were used to record transmembrane activity from the canine left ventricular epicardial, M, and endocardial regions in isolated tissue slices and arterially perfused wedge preparations. The I(Kr) blocker E-4031 (1 to 10 microM) caused prominent prolongation of action potential duration (APD) and induced EADs in tissues isolated from the M region, but not those from epicardium or endocardium, causing a large transmural dispersion of APD. In contrast, the I(Ks) blocker chromanol 293B (10 to 30 microM) produced moderate prolongation of APD without EADs in all three tissue types. The combination of E-4031 (1 microM) and chromanol 293B (30 microM) resulted in profound prolongation of APD and the development of EADs in all three tissue types. In the perfused wedge, neither E-4031 nor chromanol 293B alone could induce EADs. In combination, the two drugs caused significant prolongation of APD and EADs in all three transmural regions., Conclusion: Our results support the hypothesis that a prominent I(Ks) is responsible for the ability of epicardium and endocardium to resist some but not all of the arrhythmogenic effects of I(Kr) block. The data highlight the critical importance of I(Ks) in the canine heart and the significant role of electrotonic interactions in minimizing the development of an arrhythmogenic substrate when repolarization reserve is reduced.

Introduction: An early afterdepolarization (EAD)-induced triggered beat is thought to precipitate torsade de pointes (TdP) in the long QT syndrome (LQTS). Previous studies demonstrated the development of EAD activity and dispersion of repolarization under LQT2 (reduced I(Kr)) and LQT3 (augmented late I(Na)), but not LQT1 (reduced I(Ks)), conditions. The present study examines these electrophysiologic characteristics during I(Ks) block., Methods and Results: Canine epicardial (Epi), M, and endocardial (Endo) tissues and Purkinje fibers isolated from the canine left ventricle were studied using standard microelectrode recording techniques. The I(Ks) blocker chromanol 293B (293B, 30 microM), produced a homogeneous rate-independent prolongation of action potential duration (APD) in Epi, M, and Endo, but little to no APD prolongation in Purkinje. Chromanol 293B 1 to 30 microM failed to induce EADs or delayed afterdepolarizations (DADs) in any of the four tissue types. Isoproterenol (ISO, 0.1 to 1.0 microM) in the presence of 293B 30 microM significantly prolonged the APD of the M cell (basic cycle length > or = 1 sec), abbreviated that of Purkinje, and caused little change in that of Epi and Endo. The combination of 293B 30 microM and ISO 0.2 microM did not induce EADs in any of the four tissue types, but produced DAD activity in 4 of 8 Epi, 7 of 10 M cells, and 3 of 8 Endo., Conclusion: Our results indicate that I(Ks) block alone or in combination with beta-adrenergic stimulation does not induce EADs in any of the four canine ventricular tissue types, but that the combination of the two induces DADs as well as accentuated dispersion of repolarization.

Introduction: In canine ventricle, alpha-adrenergic agonists prolong action potential duration (APD) without any effect on the action potential notch, suggesting that, in this species, the effect on repolarization might be independent of inhibition of I(to). The present study investigated the action of the alpha-adrenergic agonist phenylephrine on the action potential and the repolarizing currents I(to) and I(K) in isolated canine epicardial myocytes., Methods and Results: Isolated cells from canine epicardial tissue, and Purkinje fibers, were studied with the whole cell, voltage clamp method. Phenylephrine 0.1 microM increased APD by 13% +/- 4% at 90% repolarization without affecting the notch or amplitude. Under voltage clamp, concentrations of phenylephrine as high as 10 microM had no effect on I(to) in canine epicardial myocytes. However, I(to) of isolated canine Purkinje myocytes was reduced to 69% +/- 7% of control by 1 microM phenylephrine. Further studies in canine epicardial myocytes revealed an action of phenylephrine to inhibit I(K), and in particular I(Ks). Using a voltage protocol that included a two-step repolarization to separate I(Ks) and I(Kr) tail components, the largely I(Kr) component was not significantly affected by 1 microM phenylephrine, whereas the largely I(Ks) component was reduced to 81% +/- 5% of control value., Conclusion: Alpha-adrenergic prolongation of repolarization in canine epicardium does not result from inhibition of I(to). Rather, it appears that reduction of I(Ks) contributes to the action of phenylephrine. The unresponsiveness of epicardial I(to) is not a general characteristic of the canine heart, because Purkinje myocyte I(to) was inhibited, suggesting regional differences in the molecular basis of I(to) and/or alpha-adrenergic signaling in the canine heart.

Introduction: Sodium pentobarbital is widely used for anesthesia in experimental studies as well as in clinics, and it is known to prevent the development of torsades de pointes (TdP) in in vivo models of the long QT syndrome (LQTS)., Methods and Results: This study examines the effects of pentobarbital on transmural dispersion of repolarization (TDR) and induction of TdP in arterially perfused canine left ventricular wedge preparations in which transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions using floating glass microelectrodes together with a transmural ECG. d-Sotalol and ATX-II were used to mimic the LQT2 and LQT3 forms of congenital LQTS. Both d-sotalol (100 micromol/L, n = 6) and ATX-II (20 nmol/L, n = 6) preferentially prolonged the action potential duration (APD90) of the M cell, thus increasing in the QT interval and TDR, and leading to the development of spontaneous and stimulation-induced TdP. In the absence and presence of d-sotalol, pentobarbital (10, 20, and 50 microg/mL) prolonged the APD90 of epicardial and endocardial cells, and, to a lesser extent, that of the M cell, thus prolonging the QT interval but reducing TDR. In the ATX-II model, the effects of pentobarbital on the QT interval and APD90 were biphasic: 10 microg/mL pentobarbital further prolonged APD90 of epicardial and endocardial cells more than that of the M cell; 20 to 50 microg/mL pentobarbital abbreviated the APD90 of epicardial and endocardial cells less than that of the M cell, thus abbreviating the QT interval and markedly reducing TDR. Twenty to 50 microg/mL pentobarbital totally suppressed spontaneous as well as stimulation-induced TdP in both models, Conclusion: Our data indicate that pentobarbital reduces TDR in control and under conditions of congenital and acquired LQTS, and suggest that this mechanism may contribute to the ability of the anesthetic to prevent the development of spontaneous as well as stimulation-induced TdP under conditions mimicking LQT2, LQT3, and acquired (drug-induced) forms of the LQTS. The data also serve to illustrate that there are circumstances under which QT prolongation may not be arrhythmogenic.

A recent publication by us has been interpreted by some as arguing against the existence and importance of M cells. We suppose this is the reason we have been asked to write this "controversy." Regrettably for the controversy, neither our work nor we deny the existence of M cells. Rather, we have confirmed, conceivably ad nauseum, that M cells do exist and contribute importantly to the expression of electrical activity in the intact myocardium. What controversy there is relates to (1) whether there is an inhomogeneous transmural gradient for ventricular repolarization in normal hearts, and (2) why the electrophysiologic properties of different myocardial sites differ so markedly at the level of the isolated tissue and single cell and yet become so much more homogenous in the intact ventricle. These issues are addressed on the following pages.

Introduction: Precipitation of torsades de pointes (TdP) has been shown to be associated with acceleration of heart rate in both experimental and clinical studies. To gain insight into the cellular mechanism(s) responsible for the initiation of acceleration-induced TdP, we studied the effect of acceleration of pacing rate in canine left ventricular epicardial, M region, endocardial, and Purkinje fiber preparations pretreated with E-4031, an IKr blocker known to induce the long QT syndrome and TdP., Methods and Results: Standard microelectrode techniques were used. E-4031 (1 to 2 microM) induced early after depolarization (EAD) activity in 31 of 36 M cell, 0 of 10 epicardial, 0 of 10 endocardial, and 9 of 12 Purkinje fiber preparations at basic cycle lengths (BCLs) > or = 800 msec. In 30 of 36 M cells, sudden acceleration from a BCL range of 900 to 4,000 msec to a range of 500 to 1,500 msec induced transient EAD activity if none existed before or increased the amplitude of EADs if already present. Acceleration-induced augmentation of EAD activity was far less impressive and less readily demonstrable in Purkinje fibers (4/12). In M cells, appearance of EAD activity during acceleration usually was accompanied by an abbreviation of action potential duration (APD). Within discrete ranges of rates in the physiologic range, acceleration caused a transient prolongation of APD in 38% of M cells, whether or not a distinct EAD was generated. Acceleration produced still more dramatic APD prolongation and EADs in M cells after the BCL was returned to the original slow rate. Epicardium and endocardium APD showed little change immediately after acceleration. A decrease of BCL as small as 10% and, in some cases, a single premature beat could promote EAD activity and APD prolongation in some M cells. Ryanodine (1 microM, 10/10), flunarizine (10 microM, 3/6), and low Na (97 vs 129 mM, 5/5) abolished the acceleration-induced EAD activity and APD prolongation as well as the EAD activity observed at slow rates in M cells pretreated with E-4031., Conclusion: Our results suggest that acceleration from an initially slow rate or a single premature beat can induce or facilitate transient EAD activity and APD prolongation in canine ventricular M cell preparations pretreated with an IKr blocker via a mechanism linked to intracellular calcium loading. Our data provide evidence in support of an important contribution of electrogenic Na/Ca exchange current to this process. These acceleration-induced changes can result in the development of triggered activity as well as a marked dispersion of repolarization in ventricular myocardium and, thus, may contribute to the precipitation of TdP in patients with the congenital (HERG defect) and acquired (drug-induced) long QT syndrome.

Introduction: K(ATP) channels are activated predominantly in the epicardium during regional ischemia. Therefore, the role of K(ATP) channels in ischemia-induced rise of extracellular potassium concentration ([K+]o) might be greater in the epicardium., Methods and Results: In 18 anesthetized dogs, the left anterior descending coronary artery (LAD) was ligated, followed by injection of 23-microm latex beads into the occluded artery to interrupt collateral flow, by which accumulated [K+]o might wash out. Epicardial and endocardial [K+]o were measured during a 20-minute period of ischemia using a valinomycin membrane. The dogs were divided into three groups: 6 control dogs (CTRL); 7 dogs pretreated with intravenous glibenclamide (0.3 mg/kg [GLIB]), a blocker of K(ATP) channels; and 5 dogs pretreated with intravenous nicorandil (0.2 to 0.25 mg/kg [NCR]), a K(ATP) channel opener. Before LAD occlusion, there was no difference in [K+]o among the three groups. In the control group, epicardial and endocardial [K+]o were increased to a similar level as a function of time after occlusion (CTRL) at both layers. Ischemia-induced epicardial [K+]o rise was suppressed by GLIB (8.4+/-0.4 vs 6.7+/-0.5 mM, P < 0.05) but augmented by NCR (12.9+/-2.0 mM, P < 0.05). In contrast, endocardial [K+]o rise remained unaffected (7.6+/-0.2 mM CTRL, 7.6+/-1.3 mM GLIB, and 9.4+/-2.2 mM NCR, P = NS)., Conclusion: Activation of K(ATP) channels plays an important role in epicardial [K+]o rise, but not in endocardial [K+]o rise, during regional ischemia. Another mechanism(s) may be important for endocardial [K+]o accumulation.

Introduction: Epicardial and endocardial defibrillation electrode systems affect myocardial electrophysiology and sympathetic function differently. Thus, we postulate that antiarrhythmic drugs will interact with these electrode systems differently., Methods and Results: Defibrillation energy requirements (DER) at 20% (ED20), 50% (ED50), and 80% (ED80) success were measured at baseline and during lidocaine (10 mg/kg per hour) or D5W treatment for epicardial and endocardial electrodes. Pigs were randomized to treatment (lidocaine or D5W) and electrode system, which resulted in four experimental groups: (1) epicardial electrode + D5W; (2) epicardial electrode + lidocaine; (3) endocardial electrode + D5W; and (4) endocardial electrode + lidocaine. ED50 DER (mean +/- SEM) values at baseline for groups 1-4 were 10.6+/-1, 8.5+/-1, 12.6+/-1, and 12.3+/-1 J, respectively. DER values for groups 1 and 3 during D5W were similar to baseline. Conversely, lidocaine increased ED50 DER values from 8.5+/-1 to 13.5+/-2 J (P < 0.05) in group 2 animals (epicardial electrodes). When lidocaine was administered to group 4 animals (endocardial electrodes), however, ED50 DER values remained similar to baseline values (12.3+/-1 to 14.3+/-2 J, P = NS). Lidocaine increased ED50 DER values by 59% with the epicardial electrode system, which was significantly greater than the 16% increase with the endocardial electrode system (P < 0.05). Electrophysiologic response and electrode impedance were similar between electrode systems., Conclusion: Lidocaine increases DER values to a greater extent when using epicardial versus endocardial electrode system. Thus, drug-device interactions are dependent on the electrode system. These data suggest that the electrophysiologic milieu created by endocardial defibrillation mitigates the effects that lidocaine has on DER values.

Introduction: Anisotropic conduction characteristics, expressed as the ratio of conduction velocities in the longitudinal (Vl) and transverse (Vt) fiber directions, may play a role in the mechanism of some ventricular tachycardias and is influenced by pharmacologic interventions. Discrepancies exist among the reported orientation-dependent effects of available Class I antiarrhythmic drugs. The aim of this study was to assess the respective effects of quinidine (Class IA), flecainide (Class IC), and cibenzoline (not subclassified) on the anisotropic conduction of porcine hearts, in corroboration of their effects on ventricular action potentials., Methods and Results: We studied the actions of 3 and 10 microM quinidine, 1 and 3 microM flecainide, and 0.3 and 1 microM cibenzoline on Vl and Vt determined from 128 electrograms recorded with a plaque electrode on the anterior left ventricle of isolated perfused hearts (spacing 2.5 mm). Vl and Vt were computed from isochronal maps displaying ellipsoid activation during stimulation from the center of the plaque. The effects on the maximal rate of depolarization (Vmax) of action potentials were obtained from ventricular muscle exposed to the same drugs. Flecainide [1 microM] and cibenzoline [0.3 microM] did not alter Vl and Vt significantly. Quinidine [3 microM] predominantly depressed Vl at rapid pacing rates, but the Vl/Vt ratio was not significantly altered. Quinidine [10 microM] and flecainide [3 microM] reduced Vl and Vt in a frequency-dependent fashion. Conversely, cibenzoline [1 microM] mostly decreased Vl and thus decreased the Vl/Vt ratio and increased the Vl/Vt at all pacing rates. This different effect was not related to a greater depressant effect on Vmax, Conclusion: Quinidine and flecainide act similarly on the anisotropic pattern of conduction (both drugs increase the Vl/Vt ratio), whereas cibenzoline exerts opposite effects. Orientation-dependent effects are different among Class I antiarrhythmic drugs and may be of importance in their therapeutic efficacy or proarrhythmic potential.