Hypoxia and Hypothermia Enhance Spatial Heterogeneities of Repolarization in Guinea Pig Hearts:

Spatial Autocorrelation of APDs During Arrhythmogenic Insults. Introduction: Regional dispersions of repolarization (DOR) are arrhythmogenic perturbations that are closely associated with reentry. However, the characteristics of DOR have not been well defined or adequately analyzed because previous algorithms did not take into account spatial heterogeneities of action potential durations (APDs). Earlier simulations proposed that pathologic conditions enhance DOR by decreasing electrical coupling between cells, thereby unmasking differences in cellular repolarization between neighboring cells. Optical mapping indicated that gradients of APD and DOR are associated with fiber structure and are largely independent of activation. We developed an approach to quantitatively characterize APD gradients and DOR to determine how they are influenced by tissue anisotropy and cell coupling during diverse arrhythmogenic insults such as hypoxia and hypothermia. Methods and Results: Voltage-sensitive dyes were used to map APs from 124 sites on the epicardium of Langendorff-perfused guinea pig hearts during (1) cycles of hypoxia and reoxygenation and (2) after 30 minutes of hypothermia (32° to 25°C). We introduce an approach to quantitate DOR by analyzing two-dimensional spatial autocorrelation of APDs along directions perpendicular and parallel to the longitudinal axis of epicardial fibers. A spatial correlation length l was derived as a statistical measure of DOR. It corresponds to the distance over which APDs had comparable values, where l is inversely related to DOR. Hypoxia (30 min) caused a negligible decrease in longitudinal θ_L (from 0.530 ± 0.138 to 0.478 ± 0.052 m/sec) and transverse θ_T (from 0.225 ± 0.034 to 0.204 ± 0.021 m/sec) conduction velocities and did not alter θ_L/θ_T or activation patterns. In paced hearts (cycle length [CL] = 300 msec), hypoxia decreased APDs (123 ± 18.2 to 46 ± 0.6 msec; P < 0.001) within 10 to 15 minutes and enhanced DOR, as indicated by reductions of l from 1.8 ± 0.9 to 1.1 ± 0.5 mm (P < 0.005). Hypothermia caused marked reductions of θ_L, (0.53 ± 0.138 to 0.298 ± 0.104 m/sec) and θ_T (0.225 ± 0.034 to 0.138 ± 0.027 m/sec), increased APDs (128 ± 4.4 to 148 ± 14.5 msec), and reduced l from 2.0 ± 0.3 to 1.3 ± 0.6 mm (P < 0.05). l decreased with increased time of hypoxia and recovered upon reoxygenation. Hypoxia and hypothermia reduced l measured along the longitudinal (l ₁) and transverse (l _T) axes of cardiac fibers while the ratio l _L/l _T remained constant.     

Decremental Conduction in the Posterior and Anterior AV Nodal Inputs

The role for fiber orientation as a determinant of conduction and block in the posterior (slow pathway, SP) and anterior (fast pathway, FP) AV nodal inputs was examined using multiple extracellular bipolar and intracellular microelectrode recordings in the superfused canine AV junction (N = 14). Results: In both inputs, antegrade longitudinal conduction velocity decremented in association with decreased action potential amplitude and dV/dt _max. A similar decrement was also present in the SP transverse to fiber orientation. SP conduction block occurred preferentially near its insertion into the compact AV node with very slow conduction (0.05 ± 0.01 M/sec) preceding conduction block. Distal antegrade FP conduction block occurred before conduction block occurred at more proximal FP sites. Conduction in the distal FP was maintained at a higher velocity (0.11 ± 0.01 M/sec, p < 0.05 vs. SP) before 2:1 conduction block was observed. Conduction velocity, action potential amplitude, and dV/dt _max were not different at any SP or FP site for paired activation transverse and longitudinal to fiber orientation. Conclusions: The data do not demonstrate a role for fiber orientation determining decremental conduction and block in transitional cell AV nodal inputs. Decremental conduction in both the SP and FP inputs is consistent with a proximal-to-distal gradient in resting membrane potential, action potential amplitude, dV/dt _max, and intracellular excitability in transitional cells during antegrade activation.     

Differential Role of Epicardial and Endocardial KATP Channels in Potassium Accumulation During Regional Ischemia Induced by Embolization of a Coronary Artery with Latex

Epicardial and and Endocardial [K⁺]₀ Rise and K_ATP Channels. 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 he 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-μm latex heads 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 he important for endocardial [K⁺]_o accumulation.     

Effect of Rate on Changes in Conduction Velocity and Extracellular Potassium Concentration During Acute Ischemia in the In Situ Pig Heart

Rate Effects on Conduction and [K⁺]_e During Ischemia. Introduction: The purpose nf our study was to determine if the slowing oflongitudinal intraventricular conduction in the in situ porcine heart during acute regional no-flow ischemia was rate dependent. Further, we investigated whether any rate dependence could he correlated to a rate-dependent component of the ischemiainduced rise in extracellular potassium concentration. [K⁺]_e. Methods and Results: We studied in situ hearts in nine anesthetized open chest pigs in which acute no-flow ischemia was induced by occlusion of the left anterior descending coronary artery. To determine the effects of steady-state rate on the slowing of conduction and rise in [K⁺]_e during ischemia, we varied the rate of stimulation during sequential occlusions from 90 to 150 beats/min. Longitudinal conduction velocity was determined by unipolar electrodes embedded in a plaque that was sutured to the epicardial surface in the center of the ischemic zone. Myocardial [K⁺]_e was determined simultaneously by potassium-sensitive electrodes placed at or within 1 to 2 mm of the epicardium in close proximity to the activation recording electrodes. Conduction vehxity decreased more rapidly at the more rapid rates of stimulation although the reduction in conduction velocity occurring prior to the onset of conduction block was similar at both rates. The potassium change was not rate dependent and rose at the same rate regardless of the rate of stimulation. Conclusion: Our study demonstrates that the steady-state rate-dependent component of the slowing of intraventricular conduction induced by acute ischemia in the in situ porcine heart occurs in the absence of a rate-dependent component in the rise of [K⁺]_e. Between rates of 90 and 150 beats/min, the rate dependence of the conduction slowing may be attributed to one or more potassium-independent factors such as the rate-dependent changes in resting membrane potential, in V?_max of the action potential upstroke, and in cell-to-cell uncoupling, which have hcen observed in other models of acute ischemia.     

The effects of procainamide on conduction in anisotropic canine ventricular myocardium

Although conduction velocity in cardiac tissue is dependent on fiber orientation, the influence of commonly used antiarrhythmic agents on conduction longitudinal and transverse to such fibers is unknown. We evaluated the effects of procainamide on conduction velocity and intracellular potentials in vitro during conduction longitudinal and transverse to fiber orientation in epicardial strips obtained from areas of uniform fiber orientation from 15 adult mongrel dogs. Ventricular epicardial strips demonstrated marked anisotropy. At a pacing cycle length of 1000 msec, mean conduction velocity longitudinal to fiber orientation averaged 0.602 +/- 0.051 m/sec and mean conduction velocity transverse to fiber orientation was 0.186 +/- 0.024 m/sec, resulting in a ratio of longitudinal to transverse conduction velocities of (theta L/T) 3.27 +/- 0.38. After the addition of procainamide, conduction velocity decreased to 0.532 +/- 0.062 m/sec longitudinal to fiber orientation and to 0.174 +/- 0.023 m/sec transverse to fiber orientation resulting in a decrease of theta L/T to 3.09 +/- 0.37 (p less than .05 vs control). Before the addition of procainamide, when pacing at progressively shorter cycle lengths, conduction velocity longitudinal to fiber orientation was relatively unchanged, whereas conduction velocity transverse to fiber orientation decreased resulting in an increase in theta L/T. After the addition of procainamide, conduction velocity at shorter pacing cycle lengths decreased both longitudinal and transverse to fiber orientation demonstrating the well-known use-dependent effect of procainamide. However, in contrast to control conditions, conduction velocity longitudinal to fiber orientation was slowed by a greater extent than the conduction transverse to fiber orientation, resulting in an even greater decrease in theta L/T. To investigate the effect of differences in drug binding during propagation in different directions, we examined conduction velocity during alternations in pacing direction and compared it with velocity during steady-state pacing. At a pacing cycle length of 1000 msec, no difference was observed between the initial conduction velocity after changing pacing directions and the steady-state conduction velocity. At pacing cycle lengths shorter than 1000 msec, when changing from transverse to longitudinal conduction, there was an initial drop in normalized conduction velocity that was present on the first beat of longitudinal conduction; however, with continued pacing in a longitudinal direction there was a further decrease in conduction velocity.(ABSTRACT TRUNCATED AT 400 WORDS)     

Modulation of Procainamide's Effect on Conduction by Cellular Uncoupling in Perfused Rabbit Hearts

Cellular Uncoupling and Procainamide's Effect. Introduction : How cell-to-cell electrical coupling influences an antiarrhythmic agent's effect on conduction is largely unknown. To investigate this, we evaluated the effects of procainamide on myocardial conduction at decreasing degrees of cell-to-cell electrical coupling induced by graded doses of heptanol.
Methods and Results : Electrograms were recorded from 50 ventricular epicardial sites in a 1 cm × 0.5 cm area during pacing to produce conduction longitudinal or transverse to myocar dial fiber orientation in Langendorff-perfused rabbit hearts. The effects of procainamide (15 mg/L.) on conduction velocity were determined in the presence of increasing doses of heptanot (0.2, 0.5, and 1.0 mM). In addition, using standard microelectrode techniques in isolated super-refused rabbit myocardium, intracellular potentials were recorded in the presence of 15 mg/L, procainamide and heptanol (1.0 mM). In the absence of heptanol, procainamide slowed conduction velocity. In the presence of increasing doses of heptanol, procainamide's contribution to the depressant effect on conduction velocity was attenuated and reversed at the highest dose. The latter effect was preferentially seen for conduction longitudinal to myocardial fiber orientation. Heptanol had no effect on action potential amplitude or maximum rate of depolarization in the presence of procainamide.
Conclusions : Procainamide's effect on conduction velocity is influenced by the underlying degree of cell-to-cell electrical coupling. The present model should he useful in evaluating the relative ability of other pharmacologic agents to modulate conduction under conditions of changing cell coupling.     

Anisotropic conduction characteristics in ischemia-reperfusion induced chronic myocardial infarction

Summary Objectives: Anisotropic properties of cardiac tissue play an important role in initiation and perpetuation of ventricular tachycardia. However, anisotropic conduction properties in different morphologic types of chronic myocardial infarctions as well as frequency dependency still need to be elucidated. In the present study, the characteristics of anisotropic conduction were investigated in situ in the setting of ischemia-reperfusion induced chronic myocardial infarction.Methods: Myocardial infarction was induced in 12 dogs by a percutaneous transcatheter left anterior descending coronary artery occlusion-reperfusion technique. Four additional dogs served as normal controls. After 14 to 20 days, epicardial mapping was performed using simultaneous unipolar recordings from 240 electrodes of a plaque electrode array placed on the epicardial border zone overlying the infarctions. Constant rate pacing with five cycle lengths (CL) ranging from 500 to 200 ms as well as programmed electrical stimulation (PES) with four basic cycle lengths (BCL) ranging from 430 to 300 ms and single extrastimuli (S2) were performed.Results: Two anatomically different patterns of epicardial surface morphology were analyzed, designated as type I and type II. In seven animals, there was a continuous thin layer of surviving epicardial muscle fibers overlying the infarction (type I). During pacing with CL of 500 vs 200 ms, conduction velocity longitudinal to fiber orientation (L) decreased significantly in the infarcted animals compared to control group (10.9% vs 5.2%,p<0.05) whereas conduction velocity transverse to fiber axis (T) decreased to a similar degree in control and infarcted animals (6.9 vs 7.4%, n.s.). After premature stimulation, there was considerably greater reduction in L in infarcted animals than in controls (39.8% vs 31.5%,p<0.05) whereas T decreased to a similar extend in infarcted and control animals (22.2% vs 21.4%, n.s.). During constant rate pacing and premature stimulation, no functional conduction block was induced in type I infarctions. In five animals, the transmural infarctions clearly extended to the epicardial surface, but continuous strands of surviving epicardial muscle fibers traversed the area of necrosis (type II). During PES with S2, functional conduction block and areas of very slow conduction were observed in each case.Conclusions: In ischemia-reperfusion induced chronic myocardial infarctions, different epicardial patterns of morphology were observed. Anisotropic conduction was frequency dependent in the longitudinal but not in the transverse direction. In type I infarctions, functional conduction block was not inducible during PES whereas in type II infarctions, prerequisites for reentrant arrhythmias like functional conduction block and very slow conduction were induced in each case by single extrastimuli.Supported by the Deutsche Forschungsgemeinschaft Grant BR 759/1-1 and 1-2.     

Rate-dependent anisotropic conduction property in the epicardial border zone of canine myocardial infarcts and its modification by moricizine

Summary We evaluated anisotropic conduction properties, different conduction velocities depending on fiber orientation, in normal and infarcted myocardium and the effects of moricizine on anisotropic conduction. Various cycle lengths of stimulation were applied to 15 mongrel dogs, and epicardial mapping was performed using a 96-channel mapping electrode. Moricizine was then administered to seven dogs and the same procedure was performed. Conduction velocities were calculated from these maps. Programmed electrical stimulations were performed before and after moricizine administration to induce ventricular arrhythmias. Before moricizine administration, a rate-dependent decrease in longitudinal conduction velocity was observed in the infarcted zone. Moricizine suppressed longitudinal conduction in the normal zone significantly at 300 msec pacing, but not at slower rates. Moricizine at a dose of 4 mg/kg, on the other hand, suppressed longitudinal conduction in the infarcted zone significantly at all pacing cycle lengths. The effect of moricizine on transverse conduction was inconsistent. In three dogs, sustained ventricular tachycardia (VT) was induced either before or after moricizine administration. The mean cycle length of sustained VT was prolonged from 202 msec to 291 msec after 4 mg/kg of moricizine. Thus, the changes in cycle length of ventricular tachycardia observed were most likely the result of slowing of conduction velocity, especially in the longitudinal direction, in the infarcted myocardium. We conclude that the electrophysiologic nature of the subacute ischemic model was modified by moricizine, leading to depression of the conduction velocity of longitudinal conduction and the inducibility of ventircular arrhythmias.     

The Renin–Angiotensin System Mediates the Effects of Stretch on Conduction Velocity,Connexin43 Expression,and Redistribution in Intact Ventricle

Effect of Stretch on Conduction and Cx43 . Introduction: In disease states such as heart failure, myocardial infarction, and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties than adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin–angiotensin system (RAS). Methods and Results: In an open‐chest canine model, a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312‐electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post‐stretch vs baseline: 51.5 ± 5.2 vs 55.3 ± 8.1 cm/s, P = 0.24, n = 11), but significantly reduced transverse conduction velocity (28.7 ± 2.5 vs 35.4 ± 5.4 cm/s, P < 0.01). It also reduced total Cx43 expression, by Western blotting, compared with nonstretched RV of the same animal (86.1 ± 32.2 vs 100 ± 19.4%, P < 0.02, n = 11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95 ± 1.4% vs control 8.74 ± 1.2%, P < 0.05). Olmesartan, an angiotensin II blocker, prevented the stretch‐induced changes in Cx43 levels, localization, and conduction. Conclusion: Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch‐induced activation of the RAS. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1276‐1283, November 2010)     

23Na NMR demonstrates prolonged increase of intracellular sodium following transient regional ischemia in the in situ pig heart

This study tests the hypothesis that Na⁺ _i increases during regional ischemia in the in situ pig heart. An extracorporeal shunt was created between the carotid artery and the left anterior descending artery of 14 open chest pigs. ²³Na and ³¹P NMR spectroscopy measured myocardial Na⁺ _i and high energy phosphates (HEPs). The protocol consisted of three 40 min periods: pre-ischemia (shunt pressure, 76±23 mmHg (S.D.)), ischemia (shunt pressure, 25±7 mmHg), and post-ischemia (shunt pressure, 53±11 mmHg). The pre-ischemia Na⁺ _i concentration was 6.7±4.2 mM. Phosphocreatine (PCr) was 15.3±0.5 mM, ATP 9.4±0.4 mM, inorganic phosphate (Pi) 1.5±0.2 mM, and pH_i 7.16±0.09. At the end of ischemia Na⁺ _i had increased to 10.5±2.8 mM (p<0.0002); PCr decreased to 5.9±2.1 mM (p<0.0002); ATP was 6.5±0.5 mM (p<0.003); Pi had increased to 6.3±1.0 mM (p<0.0002), and pH_i was 6.41±0.06 (p<0.0002). During the first 10 min of the reperfusion, Na⁺ _i increased further to 12.4±2.8 mM (p<0.025), whereas HEPs all returned to pre-ischemic values. Na⁺ _i increases during regional ischemia in the in situ pig heart, suggesting reduced Na⁺/K⁺ ATPase activity. While ATP probably does not limit Na⁺/K⁺ ATPase activity, increases in Pi and decreases in pH_i may reduce Na⁺/K⁺ ATPase activity. Additional Na⁺ _i increases during reperfusion suggest either augmented Na⁺ influx or decreased Na⁺ efflux. Received: 25 May 1998, Returned for revision: 22 June 1998, Revision received: 20 August 1998, Accepted: 15 September 1998     

Effects of propafenone on anisotropic conduction properties within the three-dimensional structure of the canine ventricular wall

Background Structural complexities of the intact ventricular wall cause a very complex spread of activation. The effects of regional tissue damage and of antiarrhythmic drugs on directional differences in activation should help to further elucidate intramural conduction patterns. Methods and results In 10 healthy dogs and in 5 dogs with subacute anterior wall infarction, 6 parallel rows of 6 needle electrodes with 4 bipolar electrode pairs per needle were inserted into the left anterior ventricular wall. Using a computerized multiplexer-mapping system, the spread of activation in epi-, endo- and midmyocardial muscle layers and in the surviving epicardium, respectively, was reconstructed. Marked differences in conduction velocities relative to fiber orientation were evident in the surviving epicardium of infarcted hearts. Directional differences in conduction velocities, although less pronounced, were still preserved throughout the intact ventricular wall. Epicardial transverse conduction in intact hearts was significantly faster than transverse conduction in infarcted hearts (0.87 ± 0.11 m/s vs 0.68 ± 0.1 m/s). In normal hearts, propafenone (2 mg/kg) decreased conduction velocities primarily in longitudinal directions (−27 ± 10%), but also moderately in transverse directions (−13 ± 7%) of all muscle layers, with no significant effect on straight (−4 ± 8%), but on oblique transmural conduction (−33 ± 18%). In infarcted hearts propafenone decreased conduction particularly in longitudinal direction (−23 ± 14%) without affecting conduction transverse to the fiber orientation (+3 ± 6%). Conclusions Longitudinal intramural shortcircuits reduce directional differences in activation. Transmural infarction results in a loss of alternative intramural pathways, unmasking marked anisotrophy in the surviving epicardium. Conduction delay in intramural pathways explains the effects of propafenone on transverse and oblique transmural conduction. Primarily longitudinal conduction delay results in reduced tissue anisotropy. Received: 8 June 2000, Returned for revision: 4 July 2000, Revision received: 20 September 2000, Accepted: 9 October 2000     

Effects of cellular uncoupling on conduction in anisotropic canine ventricular myocardium

Experiments were performed on canine superfused ventricular epicardial tissue slices to determine the effects of 1.0-2.0 mM heptanol, an uncoupling agent, on conduction longitudinal and transverse to myocardial fiber orientation. Conduction velocities were measured between proximal and distal pairs of epicardial electrodes oriented transverse and longitudinal to the direction of a conducted wavefront evoked by pacing at a basic cycle length of 2,000 msec from one margin of the tissue before and after the addition of heptanol. In a separate group of tissues, the dual bipolar orthogonal electrode was used to sequentially map epicardial activation at 40 to 45 sites in a 1 cm x 2 cm area before and 30 minutes after the introduction of heptanol. In a third group of tissues, transmembrane potentials were recorded with standard microelectrode techniques to determine the effects of heptanol on action potential characteristics. Heptanol did not significantly effect action potential amplitude or maximum rate of depolarization. After 1.0 mM heptanol, conduction velocity began to decrease in 1-2 minutes and reached a steady state in 15-20 minutes. Conduction velocity in the longitudinal direction decreased from a control value of 0.56 +/- 0.13 to 0.46 +/- 0.10 M/sec (+/- SD) at 30 minutes after heptanol (p = 0.005). In the transverse direction, it decreased from 0.24 +/- 0.09 to 0.17 +/- 0.05 M/sec (p = 0.002). The ratio of longitudinal to transverse conduction velocities increased from 2.54 +/- 1.00 to 2.94 +/- 0.82 (p = 0.042). Thus, heptanol preferentially slowed conduction in the transverse direction. Because heptanol did not greatly influence active membrane properties, we used cable equations to calculate the time course of the change in effective junctional resistivity, which rose from 133.2 omega.cm before heptanol to 312.2 omega.cm 30 minutes after heptanol administration. We conclude that heptanol slows conduction velocity by selectively increasing junctional resistivity. The preferential slowing of conduction in the transverse direction is most likely due to the fact that more junctional resistances are encountered per unit distance in the transverse than in the longitudinal direction.     

Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle

Propagation in cardiac muscle is faster in the longitudinal than in the transverse axis of the cells. Yet, as a result of the larger upstroke velocity of action potentials propagating transversely, it has been suggested that longitudinal propagation is more vulnerable to block. To study the relation between conduction velocity and maximal upstroke velocity (Vmax), as well as the time course of conduction delay and block in the transverse vs. longitudinal direction, thin square pieces of sheep epicardial muscle were superfused with the cellular uncoupler heptanol (1.5 mM). Action potentials were recorded with microelectrodes at opposite corners of the preparation while stimulating alternately in the longitudinal or transverse direction with bipolar electrodes located at contralateral corners. In all cases, block occurred more promptly for transverse than for longitudinal propagation. The decrease in conduction velocity was greater than expected for Vmax decay and, in some cases, Vmax increased while conduction velocity decreased. In the presence of high grade conduction impairment, foot potentials appeared and the upstrokes became "notched." We conclude that when intercellular coupling is impaired, transverse propagation is more vulnerable to block, and need not be dependent on changes in Vmax.     

Effect of coronary occlusion and reperfusion on local electrical resistivity of myocardium in dogs

Summary The effect of coronary occlusion and reperfusion on myocardial electrical resistivity was studied in nine anesthetized open-chest dogs. Anisotropic resistivity was measured on the anterior free wall of the left ventricle (LV) before (control) and during transient occlusion of the left anterior descending (LAD) coronary artery, and during reperfusion. To measure local resistivity longitudinal (R_L) and transverse (R_T) to epicardial muscle fiber direction, a sensor was developed based on the four electrode (FE) technique with an electrode distance of 1 mm. Previous calculations showed that measurements with this system were confined to a 2-mm-thick epicardial layer. Control values for R_L and R_T were 243±32·cm and 358±45·cm (mean±SD, n=9) respectively. During a 2-min LAD occlusion, R_L increased gradually by 12.4% (p<0.05) and R_T by 7.8% (p<0.05) above the preceding control values. During a 5-min reperfusion period resistivities returned towards control values, but tended to remain elevated. R_L showed a slight initial further increase during the first min of reperfusion and remained significantly above control values during 3 min of reperfusion. R_T returned to values not significantly different from control after about 1 min of reperfusion.     

Altered Pharmacologic Responsiveness of Reduced L-Type Calcium Currents in Myocytes Surviving in the Infarcted Heart

Altered Pharmacology of I_ca,L in Myocytes From Infarcted Heart. The pharmacologic responses of macroscopic L-type calcium channel currents to the dihydropyridine agonist, Bay K 8644, and β-adrenergic receptor stimulation by isoproterenol were studied in myocytes enzymatically dissociated from the epicardial border zone of the arrhythmic 5-day infarcted canine heart (IZs). Calcium currents were recorded at 36° to 37° C using the whole cell, patch clamp method and elicited by applying step depolarizations from a holding potential of -40 mV to various test potentials for 250-msec duration at 8-second intervals. A Cs⁺ -rich and 10 mM EGTA-containing pipette solution and a Na⁺-and K⁺-free external solutions were used to isolate calcium currents from other contaminating currents. During control, peak I_ca,L, density was found to be significantly less in IZs (4.0 ± 1.1 pA/pF) than in myocytes dispersed from the epicardium of the normal noninfarcted heart (NZs; 6.5 ± 1.8 pA/pF). Bay K 8644 (I μM) significantly increased peak I_ca,L density 3.5-fold above control levels in both NZs (to 22.5 ± 6.2 pA/pF; n = 7) and IZs (to 12.8 ± 3.0 pA/pF; n = 5), yet peak I_ca,L density in the presence of drug was significantly less in IZs than NZs. The effects of Bay K 8644 on kinetics of current decay and steady-state inactivation relations of peak I_ca,L were similar in the two cell types. In contrast, the response of peak L-type current density to isoproterenol (1 μM) was significantly diminished in IZs compared to NZs regardless of whether Ba²⁺ or Ca²⁺ ions carried the current. Thus, these results indicate an altered responsiveness to β-adrenergic stimulation in cells that survive in the infarcted heart. Furthermore, application of forskolin (1 μM and 10 μM) or intracellular cAMP (200 μM), agents known to act downstream of the β-receptor, also produced a smaller increase in peak I_Ba density in IZs versus NZs, suggesting that multiple defects exist in the β-adrenergic signaling pathway of IZs. In conclusion, these studies illustrate that reduced macroscopic calcium currents of cells in the infracted heart exhibit an altered pharmacologic profile that has important implications in the development of drugs for the diseased heart.     

Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart

Depression of myocardial conduction velocity can be an important mechanism of action of antiarrhythmic drugs but it can also facilitate arrhythmogenesis. We used lidocaine in an anesthetized canine preparation to address the hypothesis that drug-induced rate-dependent conduction velocity depression causes ventricular tachyarrhythmias. A closely spaced square array of 64 electrodes was used to determine conduction velocity longitudinal and transverse to epicardial ventricular fiber direction. Lidocaine caused rate-dependent decreases in conduction velocity that were proportionately greater in the longitudinal direction at the shortest pacing cycle lengths. Conduction velocity depression developed rapidly in the presence of lidocaine with a new steady state present by the second beat of the rapid train. Recovery from rate-dependent depression of conduction velocity was exponential with a time constant of 122 +/- 20 msec (mean +/- SD) in the longitudinal direction and 114 +/- 30 msec in the transverse direction; this difference was not significant. The relation between conduction velocity depression and ventricular arrhythmias was assessed by pacing for 3 minutes at cycle lengths of 1,000, 500, 300, and 250 msec, and for 1 minute at a cycle length of 200 msec. Arrhythmias did not occur in the baseline period in the dogs that received lidocaine, nor in 12 control dogs that were subjected to the same stimulation protocol except that saline was administered in place of lidocaine. Sustained polymorphic ventricular tachycardia (VT) occurred in six of 16 dogs given lidocaine. VT occurred in the presence of relatively high plasma lidocaine concentrations (8.4 +/- 2.3 micrograms/ml) and only at pacing cycle lengths of 300 msec or shorter. The dogs that developed VT demonstrated greater rate-dependent depression of conduction velocity than the other dogs, and activation patterns obtained just before the onset of VT showed marked conduction disturbances. Furthermore, QRS prolongation, loss of one-to-one capture, and increasingly distorted activation patterns preceded the onset of VT during fixed-rate pacing, suggesting progressive sodium channel block. In summary, rate-dependent conduction velocity depression and nonuniform activation were associated with VT in this model and can be responsible for some arrhythmias induced by antiarrhythmic drugs.     

Plasma Exchange Downregulates Activated Monocytes and Restores Regulatory T Cells in Kawasaki Disease

In Kawasaki disease (KD), the effect of plasma exchange (PE) on immune cells has not been fully elucidated. Therefore, we examined the changes in the number of CD14⁺ CD16⁺ activated monocytes, regulatory T (T_reg), and T‐helper type 17 (Th17) cells in KD patients treated with PE. The percentage of total monocytes and subclasses of lymphocytes, including CD4⁺ and CD8⁺ T cells, and CD19⁺ B cells, showed no significant difference before and after PE. However, the percentage of CD14⁺ CD16⁺ monocytes in total leukocytes decreased significantly after PE (1.1% ± 1.5% vs. 2.1% ± 2.3%, P < 0.05). Furthermore, while the percentage of Th17 cells in CD4⁺ T cells did not change, the percentage of T_reg cells in CD4⁺ T cells increased significantly after PE (11.1% ± 5.1% vs. 8.0% ± 4.4%, P < 0.05). Therefore, PE downregulates activated monocytes and upregulates T_reg cells toward normal levels and thus attenuates inflammation in KD.     

The effect of enhanced gap junctional conductance on ventricular conduction in explanted hearts from patients with heart failure

Aim  To investigate ventricular conduction and refractoriness before and after application of rotigaptide, an enhancer of gap junctional conductance, to explanted hearts of patients with heart failure (HF). Methods and results  In six explanted perfused hearts of patients with end-stage HF, activation/repolarization mapping was performed and refractory periods (RPs) and activation recovery intervals (ARIs) were measured before and after application of 50 nM rotigaptide. Rotigaptide caused a decrease of RP from 476 ± 36 to 453 ± 31 ms (P < 0.05), but did not change ARI-dispersion. During premature activation along the fibers rotigaptide decreased the minimal activation time (AT_min) and maximal activation time (AT_max) significantly from 35 ± 12 to 24 ± 9 and from 97 ± 38 to 43 ± 7 ms, respectively. Rotigaptide did not change AT_min and AT_max during activation perpendicular to the fiber direction. After application of rotigaptide conduction curves normalized in five/six recordings when activation was parallel, but destabilized in three/six hearts when activation was perpendicular to fiber direction. The destabilization was associated with local conduction delays rather than with facilitation of conduction. Conclusion  Rotigaptide applied to hearts of patients with end-stage HF shortened RPs normalized conduction curves and increased conduction parallel to fiber direction. However, in 50% of the hearts local slowing of conduction with destabilization of conduction (curves) occurs at sites close to the stimulation site, when activation is perpendicular to fiber direction. Returned for 1. Revision: 14 July 2008 1. Revision received: 26 August 2008 Returned for 2. Revision: 19 September 2008 2. Revision received: 31 October 2008 Returned for 3. Revision: 17 November 2008 3. Revision received: 18 November 2008     

Effect of scar and His–Purkinje and myocardium conduction on response to conduction system pacing

Introduction

Conduction system pacing (CSP), in the form of His bundle pacing (HBP) or left bundle branch pacing (LBBP), is emerging as a valuable cardiac resynchronization therapy (CRT) delivery method. However, patient selection and therapy personalization for CSP delivery remain poorly characterized. We aim to compare pacing-induced electrical synchrony during CRT, HBP, LBBP, HBP with left ventricular (LV) epicardial lead (His-optimized CRT [HOT-CRT]), and LBBP with LV epicardial lead (LBBP-optimized CRT [LOT-CRT]) in patients with different conduction disease presentations using computational modeling.

Methods

We simulated ventricular activation on 24 four-chamber heart geometries, including His–Purkinje systems with proximal left bundle branch block (LBBB). We simulated septal scar, LV lateral wall scar, and mild and severe myocardium and LV His–Purkinje system conduction disease by decreasing the conduction velocity (CV) down to 70% and 35% of the healthy CV. Electrical synchrony was measured by the shortest interval to activate 90% of the ventricles (90% of biventricular activation time [BIVAT-90]).

Results

Severe LV His–Purkinje conduction disease favored CRT (BIVAT-90: HBP 101.5 ± 7.8 ms vs. CRT 93.0 ± 8.9 ms, p < .05), with additional electrical synchrony induced by HOT-CRT (87.6 ± 6.7 ms, p < .05) and LOT-CRT (73.9 ± 7.6 ms, p < .05). Patients with slow myocardium CV benefit more from CSP compared to CRT (BIVAT-90: CRT 134.5 ± 24.1 ms; HBP 97.1 ± 9.9 ms, p < .01; LBBP: 101.5 ± 10.7 ms, p < .01). Septal but not lateral wall scar made CSP ineffective, while CRT was able to resynchronize the ventricles in the presence of septal scar (BIVAT-90: baseline 119.1 ± 10.8 ms vs. CRT 85.1 ± 14.9 ms, p < .01).

Conclusion

Severe LV His–Purkinje conduction disease attenuates the benefits of CSP, with additional improvements achieved with HOT-CRT and LOT-CRT. Septal but not lateral wall scars make CSP ineffective.     

Pharmacological Activation of IKr Impairs Conduction in Guinea Pig Hearts

Activation of I_Kr Impairs Conduction. Introduction: The hERG (Kv11.1) potassium channel underlies cardiac I_Kr and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I_Kr results in impaired cardiac conduction. Methods and Results: Cardiac conduction was assessed in Langendorff‐perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 μM) prolonged the QRS rate dependently. A significant prolongation (16 ± 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I_Kr blocker E4031 (1 μM). While partial I_Na inhibition with flecainide (1 μM) alone prolonged the QRS (34 ± 3%, BCL 250 ms), the QRS was further prolonged by 19 ± 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di‐4‐ANEPPS a similar potentiation of the effect of NS3623 was observed. With di‐4‐ANEPPS, NS3623 prolonged the QRS significantly (26 ± 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. Conclusion: Pharmacological activation of I_Kr by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I_Kr in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs. (J Cardiovasc Electrophysiol, Vol. 21, pp. 923‐929, August 2010)