Limitations of bipolar and unipolar conditioning stimuli for inhibition in the human heart

Noncapturing, conditioning electrical stimuli (Sc) delivered within the ventricular refractory period can prolong refractoriness and prevent later stimuli from eliciting a propagated response (inhibition). The purpose of this study was to further define the spatial effects of Sc, to determine if the effects of Sc can be enhanced by the use of unipolar as opposed to bipolar stimulation, and to evaluate the effect of Sc on the physiologic spread of excitation during atrioventricular reentry tachycardia. In 23 patients the right ventricular refractory period was determined before and after the introduction of bipolar, unipolar cathodal, and unipolar anodal noncapturing Sc with pulse widths of 2 or 9 msec and strengths of twice diastolic threshold and 10 MA. Pacing and conditioning stimuli were delivered at the same site and at sites separated by 3 mm. During ventricular pacing both bipolar and unipolar Sc prolonged the ventricular refractory period by greater than or equal to 10 msec in 22 of 23 patients when both Sc and pacing stimuli were delivered to the same site. However, when Sc was delivered 3 mm away from the pacing stimuli, the ventricular refractory period increased by greater than or equal to 10 msec in only 1 of 17 patients who received bipolar Sc and in none of 13 patients who received unipolar Sc. In seven patients bipolar conditioning stimuli were delivered as close as possible to the atrial insertion of an accessory atrioventricular connection during circus movement tachycardia with a well-localized accessory pathway. Sc did not terminate or slow tachycardia in any patient.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in canine ventricular refractoriness induced by trains of subthreshold high-frequency stimuli

Epicardial electrodes were applied to 12 thoractomized dogs to determine the effects of trains of subthreshold conditioning stimuli (TSc) on ventricular refractoriness when delivered preceding a premature suprathreshold stimulus (S2). Several factors were analyzed: (1) the influence of TSc pulse frequency (100-900 Hz); (2) the delay between TSc and S2 (1 or 10 ms); (3) the distance between the electrodes for the emission of TSc and S2 (same electrodes or different electrodes at 3 mm); and (4) S2 current intensity (two- or fourfold diastolic threshold). The TSc (mean current intensity 0.33 mA, range 0.1-0.7) were found to significantly prolong the effective ventricular refractory period (EVRP) at all train pulse frequencies. The EVRP increment was progressively greater as pulse frequency was increased, the maximum EVRP increment being at 900 Hz (mean 50.8 +/- 32.3 ms; maximum increment 130 ms). On increasing S2 current intensity, the EVRP increment was less (maximum value 35 ms) and less consistent (in four of six dogs); in two cases the EVRP was shortened. The increase in delay between TSc and S2 attenuated the EVRP prolongation, which was present in only three of six dogs tested, and the EVRP was shortened in two dogs. There was no EVRP prolongation at any TSc pulse frequency when TSc and S2 were delivered at different electrodes. Thus TSc decreases myocardial ventricular excitability, prolonging EVRP in direct proportion to TSc pulse frequency. However, this property is limited by S2 current intensity as well as the time and distance between TSc and S2.     

Block of cardiac sodium channels by antiarrhythmic drugs

The effects of seven Class-I antiarrhythmic drugs on the maximum upstroke velocity (Vmax) of action potential were examined in isolated guinea pig ventricular muscles in order to characterize their use- and state-dependent sodium channel blocking action. From the onset and offset kinetics of the use-dependent Vmax inhibition during stimulation trains, the seven drugs were subdivided into two groups; fast drugs (lidocaine, mexiletine, and tocainide), and slow drugs (quinidine, aprindine, disopyramide and flecainide). In experiments to assess the state-dependent sodium channel block, a conditioning clamp pulse to 0 mV was applied by using the single sucrose-gap voltage-clamp technique, and the Vmax of test action potential 100 msec after the clamp pulse was measured. The decrease in Vmax by 10 msec clamp pulse was defined as the activated channel block (ACB), and the decrease in Vmax as the clamp pulse duration was prolonged from 10 to 500 msec was defined as the inactivated channel block (ICB). The ratio of ICB to ACB was less than 1.0 for quinidine, disopyramide and flecainide, and much greater than 1.0 for aprindine, lidocaine, mexiletine, and tocainide. These characteristics may contribute to the differences in efficacy of each drug in treating various types of arrhythmias.     

Conditioning prepulse of biphasic defibrillator waveforms enhances refractoriness to fibrillation wavefronts

The mechanism of biphasic waveform defibrillation threshold reduction is unknown. We tested the hypothesis that, during refractory period stimulation, sarcolemmal hyperpolarization by the first pulse of biphasic waveforms facilitates excitation channel recovery, which enhances graded responses produced by the second depolarizing pulse. This prolongs cellular refractoriness to fibrillation wavefronts when compared with a monophasic depolarizing stimulus. Monophasic (10 msec, rectangular wave) or symmetrical biphasic (10 msec, each pulse) current injection S2 stimuli at 1.5 and two times S1 threshold were used to scan the S1 action potential refractory period (S1 cycle length, 600 msec) in myocardial cell aggregates. S2 waveforms were delivered with normal and reversed polarity to test the hyperpolarizing action of biphasic waveforms. Responses to an S3 stimulus, which simulated a potential incoming fibrillation wavefront, were also determined. Results showed that biphasic S2 waveforms produced longer graded responses during and immediately after the S1 refractory period than did corresponding monophasic S2 waveforms. The maximum difference in response duration produced by the biphasic and monophasic waveforms was 58.6 +/- 10.0 msec (p less than 0.001). This maximum difference occurred 10 msec before the end of the S1 refractory period. The longer response durations produced by biphasic S2 also produced longer refractoriness to the S3 stimulus. The maximum difference in total refractoriness to S3 of 51.8 +/- 2.8 msec (p less than 0.002) occurred at the same S1S2 coupling interval as the maximum difference in S2 response duration. Prolonged refractoriness may protect ventricular cells from refibrillation wavefronts and act as the cellular basis for greater biphasic waveform defibrillation efficacy.     

Entrainment by an Extracellular AC Stimulus in a Computational Model of Cardiac Tissue

INTRODUCTION: Cardiac tissue can be entrained when subjected to sinusoidal stimuli, often responding with action potentials sustained for the duration of the stimulus. To investigate mechanisms responsible for both entrainment and extended action potential duration, computer simulations of a two-dimensional grid of cardiac cells subjected to sinusoidal extracellular stimulation were performed. METHODS AND RESULTS: The tissue is represented as a bidomain with unequal anisotropy ratios. Cardiac membrane dynamics are governed by a modified Beeler-Reuter model. The stimulus, delivered by a bipolar electrode, has a duration of 750 to 1,000 msec, an amplitude range of 800 to 3,200 microA/cm, and a frequency range of 10 to 60 Hz. The applied stimuli create virtual electrode polarization (VEP) throughout the sheet. The simulations demonstrate that periodic extracellular stimulation results in entrainment of the tissue. This phase-locking of the membrane potential to the stimulus is dependent on the location in the sheet and the magnitude of the stimulus. Near the electrodes, the oscillations are 1:1 or 1:2 phase-locked; at the middle of the sheet, the oscillations are 1:2 or 1:4 phase-locked and occur on the extended plateau of an action potential. The 1:2 behavior near the electrodes is due to periodic change in the voltage gradient between VEP of opposite polarity; at the middle of the sheet, it is due to spread of electrotonic current following the collision of a propagating wave with refractory tissue. CONCLUSION: The simulations suggest that formation of VEP in cardiac tissue subjected to periodic extracellular stimulation is of paramount importance to tissue entrainment and formation of an extended oscillatory action potential plateau.     

Sequential or single pulse defibrillation? Investigations towards energy reduction in experimental animals

With introduction of the automatic implantable cardioverter-defibrillator for treatment of medically refractory ventricular arrhythmias, many investigations are focussing on possibilities of reducing the energy necessary for defibrillating the heart to obtain a more adequate size and a longer durability of the generator. Several studies favour the sequential pulse delivery, using three electrodes, either endocardial, epicardial or subcutaneous plates, to improve defibrillation performance of low energy shocks. However, the validity of this conclusion remains equivocal since two different electrode configurations were used for single and sequential defibrillation. In the present study the influence of sequential pulse delivery, pulse sequence and resultant current pathways on defibrillation energy requirements were examined in comparison with single-shocks between the same epicardial electrode configuration as well as four orthogonally positioned patches. The energy requirement for 100% efficiency could be reduced by sequential pulsing with a time interval of 1 msec thus yielding significant superiority compared to single pulse defibrillation using three electrodes. The same reliable defibrillation and reduced threshold has been obtained by using four electrodes and one single shock. The addition of a third electrode alone had no influence on the energy requirements. Therefore, we have to discuss a different electrophysiological mechanism for sequential defibrillation than for single shocks with an extended current distribution over the heart using four electrodes. Possibly the action potential of the single cell of the fibrillating heart is of interest in reflecting the efficiency of sequential pulse defibrillation. By influencing the action potential pharmacologically in some animals, the optimal time interval for double shocks could be extended up to 7 msec.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of Shock-Induced Action Potential Extension During Acute Regional Ischemia in Rabbit Hearts

Shock Effects During Ischemia. Introduction: Defibrillation shocks produce extension of the myocardial action potential repolarization time (AP extension) in nonischemic myocardium. AP extension may synchronize repolarization in the heart because the extension increases when shock timing is increased. We tested whether AP extension occurs and whether it increases when shock timing is increased in regionally ischemic isolated perfused rabbit hearts stained with the transmembrane voltage sensitive fluorescent dye, di-4-ANEPPS and given diacetyl monoxime to eliminate motion artifacts. Methods and Results: Before and after left anterior descending (LAD) coronary artery occlusion, APs were recorded on the anterior left ventricular epicardium with an epifluorescence measurement system. Hearts were paced with a train of 10 stimuli (SI) and then during the 10th AP were given a defibrillation shock (S2) from epicardial electrodes on either side of the recording region. Before LAD occlusion, duration of the 9th SI-induced AP measured at full repolarization was 171 ± 11 msec (mean ± SD). Within 15 minutes after LAD occlusion, the AP duration became shorter (P < 0.05) and more variable (137 ± 42 msec), and APs with negligible plateaus were observed. Extension of the 10th AP by S2 was significant both before (mean extension of 59 to 65 msec for three S2 waveforms tested) and after LAD occlusion (mean extension of 35 to 41 msec). Unlike the results before LAD occlusion, AP extension after occlusion was independent of absolute shock timing expressed in msec. When timing was expressed as a fraction of individual AP durations, AP extension after occlusion increased with increases in shock timing. Conclusions: Shocks extend Aps during ischemia; however, absolute time dependence of AP extension is not constant among cells that have different AP durations during Ischemia. This may influence postshock repolarization synchrony when different AP durations exist in different parts of regionally ischemic hearts.     

Concurrent Failure of Active and Redundant Ventricular Epicardial Electrodes in Children

Implanting an unused or redundant epicardial ventricular pacing electrode in children at the time of initial electrode placement for later use is a common practice. To investigate the ultimate utilization of this redundant electrode, the records of 38 children who had undergone implantation of 47 redundant epicardial electrodes between 1974 and 1987 were reviewed. As the primary electrode remains functional, 12 electrodes have not been in-vasively tested or used; 11 were in nine children lost to follow-up. The remaining 24 redundant electrodes implanted in 16 children, (ages 1 day to 18 years, median 5 years, at implantation) together with the utilized electrode were evaluated at the time of pacing system revision. At implant, all electrodes had thresholds < 1.4 volts at a pulse duration of0.5 msec. At follow-up 0.2 to 11.7 years (mean 3.7 years) after implant, an electrode was considered functional if the threshold at 0.5 msec pulse duration was < 2.5 volts, and 14 of 24 redundant electrodes were nonfunctional. Of the ten functional redundant electrodes, the active electrode was functional in seven cases. In only three of 24 cases was the redundant electrode functional when the active electrode was nonfunctional. In all cases, when the active electrode exhibited exit block, the redundant electrode also exhibited exit block. Two of five redundant electrodes paired with a fractured active electrode were fractured. Two other redundant electrodes were fractured when the active electrode was functional. The state of the redundant and the active electrode was the same in 80% of the cases, P < 0.03. Of the 36 redundant electrodes implanted for which follow-up data is available, 33 had not been used by the end of the study period. (J Interven Cardiol 1989:2:1)     

A new intracavitary probe for detecting the site of origin of ectopic ventricular beats during one cardiac cycle

An olive-shaped probe (25 X 12 mm) with 41 evenly distributed recording electrodes on its surface was introduced into the left ventricles of seven open-chest dogs via the left atrium. In two other dogs a cylindrical probe (40 X 3 mm) was used. Electrical stimuli were delivered at 66 endocardial, midwall, or epicardial sites in the left and right ventricular walls and the septum. Mechanical stimuli were also applied at various epicardial sites. On-line mapping of equipotential contour lines on the surface of the probe invariably revealed a clear-cut potential minimum on the electrode that faced the pacing site. Time of appearance of potential minimum was 3 to 5 msec after endocardial stimuli, 10 to 25 msec for midwall and epicardial pacing, and 30 msec or more for right ventricular stimulation. Simultaneous stimulation at two sites 1.2 cm apart gave rise to two separate minima on the maps. "Pseudoisochrones" derived from electrograms recorded by the new probe were slightly less accurate in indicating the site of origin of extrasystoles. We conclude that equipotential and "isochrone" contour maps recorded from an array of semidirect electrodes, regularly distributed on the surface of an intraventricular probe, provide information on the site of origin (location and intramural depth) of ectopic paced beats in a normal dog heart.     

Thresholds for transesophageal atrial pacing

To determine the thresholds for transesophageal atrial capture, as well as factors that may influence the thresholds, we measured the minimal current and pulse width required to pace the atria through transesophageal bipolar lead systems in 12 patients, ranging in age from 1 day to 19 years, during 19 episodes of reentrant supraventricular tachycardia. Depending on the patients' age and size several electrode catheters were used. The protocol called for 1-msec step-wise increments in pulse width. At each pulse width the current was increased by 1 mamp until capture was achieved. The mean minimal pulse width and mean minimal current required for capture were 5.8 msec and 13.6 mamp, respectively. Atrial capture was achieved in 75% of attempts at a pulse width and current equal to or less than 6.5 msec and 17.5 mamp, respectively. No correlation between current and pulse width on the one hand and age, height, weight, or body surface area on the other was detected. Likewise neither electrode type nor existence of structural heart disease influenced the threshold required for capture. We conclude that atrial capture can be readily achieved through transesophageal electrodes and is not influenced by the subject's age or size.     

Inhibition by trains of subthreshold high-frequency stimuli: an experimental study in spatial limitation.

The aim of this study was to determine whether the spatial limitation of the inhibitory effect of subthreshold conditioning stimuli trains (TSc) could be overcome by their simultaneous emission through several electrodes surrounding the area where the suprathreshold extrastimuli (S2) are delivered. In seven anesthaetized open chest dogs the effective ventricular refractory period was determined before and after the introduction of unipolar cathodal TSc, using epicardial electrodes. TSc pulse frequencies tested were 100 Hz, 200 Hz, 400 Hz, 600 Hz and 800 Hz, and train intensity was 10% lower than the train diastolic threshold for every pulse frequency. S2 and TSc were delivered: (a) by the same electrode; (b) by two different electrodes 3 mm apart; and (c) TSc through six peripheral electrodes surrounding the central electrode that delivered S2 (heptapolar electrode). Trains of 400 Hz showed the highest diastolic threshold, permitting the use of the highest train intensities. When TSc and S2 were delivered through the same electrode the ventricle remained unexcitable during the entire cardiac cycle in six of the seven dogs. In turn, when TSc and S2 were delivered by two different electrodes, the effective ventricular refractory period (EVRP) could only be increased by greater than or equal to 10 ms in three of the seven dogs (18 ms, 62 ms and 10 ms). When TSc was delivered simultaneously through six peripheral electrodes the increments were higher (118 ms, 88 ms and 75 ms) in these three dogs, and there was one additional dog with 12 ms increments of of EVRP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevention of Action Potentials During Extracellular Electrical Stimulation of Long Duration

Prevention of Action Potentials by Electrical Stimulation. Introduction : This study investigated if action potentials can be prevented by electrical field stimuli of long duration.
Methods and Results : The transmembrane potential was recorded by a double-barrel micro-electrode during field stimulation given across a papillary muscle from 10 guinea pigs. After 10 stimuli (S) with a 200-msec S-S interval, a 400-msec square wave shock was given Just before or after the end of the effective refractory period following the 10th stimulus through electrodes 1 cm on either side of the papillary muscles. Another two stimuli (S' and S") having the same 200-msec S-S interval were given during the shock pulse to test if the action potentials induced by these two stimuli could be prevented by the shock. The shock strength was increased until the shock field prevented the action potentials induced by the S' and S" stimuli. The resting membrane potential was −85.5 ± 2.9 mV. For shocks causing depolarization at the recording site, the field strength required to prevent S'- and S"-induced action potentials was 1.5 ± 0.4 V/cm, which depolarized the transmembrane potential to −55.3 ± 8.9 mV and −58.1 ± 7.2 mV from the resting membrane potential at the time of the S' and S" stimuli, respectively. The strength of shocks causing hyperpolarization required to prevent S'- and S"-induced action potentials was 5.0 ± 0.8 V/cm, which hyperpolarized the transmembrane potential to −105 ± 6.5 mV and −115.6 ± 6.9 mV from the resting membrane potential at the time of the S' and S" stimuli, respectively.
Conclusion : Both depolarization and hyperpolarization caused by an electrical field can prevent action potentials.     

Effect of changes in inputs to atrioventricular node on AV conduction.

The effect of different inputs into the atrioventricular node (AVN) on orthograde impulse transmission was studied. In rabbit AVN preparations, two stimulating electrodes were placed posteriorly in the crista terminalis (P) and anteriorly in the interatrial septum (A). Electric stimuli were given individually (P,A) or simultaneously (P + A). Premature stimulation, when properly timed (e.g. 70-100 msec at the basic cycle length of 400 msec) achieved AV conduction only in P + A but not in either P or A. Action potentials (APs) in AVN in this situation revealed an incomplete depolarization in P and A, but became a fullsized AP in P + A. This might be explained by summation. The site of simmation appeared to be in the upper node, because APs distal to the middle node as well as APs in the His bundle behaved in an "all or none" fashion. Time intervals between the stimulus artifact and the His bundle AP upstroke (S-H) were shorter in P + A was enhanced with the decrease of the S-H difference between P and A suggested an accelerated conduction by summation in AVN. A hyperpolarizing current flowing through the suction electrodes which were attached in the vicinity of AVN caused different amounts of S-H shortening between P and A input. The above data support the view that AVN has a summating property engendered by the slow inactivation of ionic channel on which the upstroke of AP depends and by the limited number and sites of atrial inputs which might connect with some preferential paths within the AVN.     

Facilitation of Ca2+-channel currents in bovine adrenal chromaffin cells.

Ca2+-channel currents in primary cultures of bovine adrenal chromaffin cells were studied using the whole-cell patch-clamp method. Parameters of a double-pulse protocol were systematically varied to characterize facilitation by a prepulse (P1) of Ca2+-channel current during a test pulse (P2). The pulses were usually separated by 30 msec, an interval sufficient for decay of any measurable P1 tail currents. The Ca2+-channel current amplitude during P2 increased when P1 voltage was more positive than 0 mV. The effect became progressively greater with more positive P1 voltage. With a 60-msec P1 to +80 mV, the current amplitude typically increased by 25%-35% during a 60-msec P2. Comparison of facilitated and control inward Ca2+-channel current I(V) curves showed that facilitation was also strongly dependent on P2 test voltage. Facilitation of Ca2+-channel currents is a voltage-dependent phenomenon and is not dependent on Ca2+ entry. When short repetitive voltage-clamp pulses were applied, the Ca2+-channel current amplitude increased with each pulse. This suggests that Ca2+-channel facilitation could enhance release of catecholamines from chromaffin cells during a train of action potentials.     

Perceptual Hyperreactivity to Auditory Stimuli in Patients with Irritable Bowel Syndrome

Background: Patients with irritable bowel syndrome (IBS) have abnormal perception of visceral stimuli; however, no study has so far investigated the perception of non-visceral stimuli in IBS. In the present study we used event-related potentials (ERP) to study whether IBS patients differed from healthy controls in processing of auditory stimuli and, if so, how this was influenced by emotions. Methods: We compared ERPs to auditory stimuli in 40 female diarrhoea-predominant IBS patients without current psychiatric illness with those in 20 healthy controls. Tones were used as standard and target stimuli, and words with emotional content as distractors. Characteristics of the first negative wave (N100) and mean amplitudes in 50-msec time intervals between 150 and 600 msec were assessed. Results: At the frontal midline electrode IBS patients had significantly enhanced N100 amplitude to all stimuli, persisting after adjustment for age, current emotions, and personality traits. They additionally had enhanced waves 200-300 msec and 400-500 msec after stimulus. The latter differences disappeared after adjustment for emotions and personality traits. Conclusions: In the frontal brain region, IBS patients seem to have a hyperreactivity to auditory stimuli compared with controls. Later elements (P300, N400) of stimulus processing were influenced by emotions and personality traits. These may possibly contribute to changes in intestinal motility caused by stress. The study indicates that aberrant brain functioning may be an element of the irritable bowel syndrome. It may elucidate a mechanism for brain-gut interaction by which psychosocial stress may influence visceral pain perception in non-psychiatric subjects with an intestinal motility disorder and also the efficacy of psychiatric treatment on IBS symptoms.     

The safety factor for electroventilation measured by production of cardiac ectopy in the anesthetized dog

The safety factor of electroventilation (ie, the ratio of the current required to produce an ectopic beat to the current required to produce an inspired volume of 225 ml, which is approximately twice tidal volume) was determined in 12 pentobarbital-anesthetized dogs using transthoracic electrodes positioned at the optimal electroventilation site. The optimal stimulation site for electroventilation was first determined using hand-held, stimulating electrodes. Then electrodes, 4.1 cm in diameter, were sutured bilaterally to the optimal stimulation site. The relationship between inspired volume and stimulus intensity was determined using a 0.8-s burst of stimuli (60/s) with a pulse duration of 0.1 ms. Using the same electrodes, the threshold current for producing ectopic beats was determined for single pulses ranging from 0.1 to 10 ms duration. In all dogs, the current required to produce an ectopic beat increased greatly as the pulse duration decreased. At 0.1 ms, the safety factor for electroventilation was calculated to be 25.8.     

Monophasic Action Potential Recordings from Intact Mouse Heart: Validation, Regional Heterogeneity, and Relation to Refractoriness

INTRODUCTION: The monophasic action potential (MAP) technique has been validated in humans and larger animals, but, in mice, MAP recordings available to date show little resemblance to the murine ventricular transmembrane action potential (TAP) measured by conventional microelectrodes. We developed a miniaturized MAP contact electrode technique to establish in isolated mouse hearts: (1) optimal electrode size; (2) validation against TAP; (3) relationship between repolarization and refractoriness; and (4) regional repolarization differences. METHODS AND RESULTS: In 30 Langendorff-perfused mouse hearts, MAP electrodes of tip diameter 1.5, 1.0, and 0.25 mm were tested by comparing MAPs and TAPs from epicardial and endocardial surfaces of both ventricles. Only the MAP contact electrode of 0.25-mm tip diameter consistently produced MAP recordings that had wave shapes nearly identical to TAP recordings. MAP durations measured at 30%, 50%, 70%, and 90% repolarization (APD30, APD50, APD70, APD90) highly correlated with TAP measurements (r = 0.97, P < 0.00001). APD50 was significantly longer in endocardial than in epicardial recordings (right ventricle: 9.3+/-1.1 msec vs 3.9+/-1.1 msec; left ventricle: 9.9+/-2.1 msec vs 6.2+/-1.9 msec; both P < 0.001), demonstrating transmural repolarization differences. Effective refractory period (ERP) determined at basic cycle lengths from 70 to 200 msec correlated with 80%+/-6% of total repolarization, with an ERP/APD90 ratio of 0.85+/-0.14. CONCLUSION: Murine myocardial repolarization, regional repolarization heterogeneity, and relation to refractoriness can be assessed reliably by this miniaturized MAP contact electrode technique, which renders action potential wave shapes similar to that of intracellular microelectrodes. This technique may be useful for exploring repolarization abnormalities in genetically altered mice.     

Comparison of the Rate-Dependent Properties of the Class III Antiarrhythmic Agents Azimilide (NE-10064) and E-4031

Rate Dependence of Azimilide and E-4031. Introduction : Reverse rate-dependence, a lessening in Class III antiarrhythmic agent action potential duration (APD) prolongation as heart rate is increased, has been proposed to be related to an incomplete deactivution of the slow component (I_Ks) of the delayed rectifier K⁺ current (I_K). The rate-dependent properties of block of I_K by azimilide were compared to E-4031, which selectively blocks the rapid component (I_Kr) of I_k, in guinea pig ventricular muscle.
Methods and Results : Azimilide prolonged APD in isolated papillary muscles in a concentration-dependent manner and to a greater degree than E-4031. Both agents prolonged APD less at fast than slow rates, consistent with a similar reverse rate-dependent effect. Isolation of azimilide block of I_Ks by subtraction of APD during E-4031 plus azimilide from E-4031 alone revealed rate-independent prolongation of APD. In voltage clamp experiments on single ventricular myocytes, activation of I_ks was similar following 30 seconds of conditioning pulses of physiological duration (125 to 200 msec) with either a fast (cycle length 250 msec) or slow (cycle length 2000 msec) rate. The block of I_Ks by azimilide 3 μM was greater after a fast conditioning pulse train.
Conclusions : Selective block of I_ks prolongs APD in a rate-independent manner. In voltage clamped myocytes, no evidence of a rate-dependent accumulation of I_Ks was observed. These findings support a mechanism of reverse rate-dependent APD prolongation by Class III antiarrhythmic agents that block I_Kr independent of I_Ks.     

Perceptual hyperreactivity to auditory stimuli in patients with irritable bowel syndrome

BACKGROUND: Patients with irritable bowel syndrome (IBS) have abnormal perception of visceral stimuli; however, no study has so far investigated the perception of non-visceral stimuli in IBS. In the present study we used event-related potentials (ERP) to study whether IBS patients differed from healthy controls in processing of auditory stimuli and, if so, how this was influenced by emotions. METHODS: We compared ERPs to auditory stimuli in 40 female diarrhoea-predominant IBS patients without current psychiatric illness with those in 20 healthy controls. Tones were used as standard and target stimuli, and words with emotional content as distractors. Characteristics of the first negative wave (N100) and mean amplitudes in 50-msec time intervals between 150 and 600 msec were assessed. RESULTS: At the frontal midline electrode IBS patients had significantly enhanced N100 amplitude to all stimuli, persisting after adjustment for age, current emotions, and personality traits. They additionally had enhanced waves 200-300 msec and 400-500 msec after stimulus. The latter differences disappeared after adjustment for emotions and personality traits. CONCLUSIONS: In the frontal brain region, IBS patients seem to have a hyperreactivity to auditory stimuli compared with controls. Later elements (P300, N400) of stimulus processing were influenced by emotions and personality traits. These may possibly contribute to changes in intestinal motility caused by stress. The study indicates that aberrant brain functioning may be an element of the irritable bowel syndrome. It may elucidate a mechanism for brain-gut interaction by which psychosocial stress may influence visceral pain perception in non-psychiatric subjects with an intestinal motility disorder and also the efficacy of psychiatric treatment on IBS symptoms.     

Ventricular fibrillation induced by stretch pulse: implications for sudden death due to commotio cordis

Introduction: Nonpenetrating chest wall impact (commotio cordis) may lead to sudden cardiac death due to the acute initiation of ventricular fibrillation (VF). VF may result from sudden stretch during a vulnerable window, which is determined by repolarization inhomogeneity.
Methods: We examined action potential morphologies and VF inducibility in response to sudden myocardial stretch in the left ventricle (LV). In six Langendorff perfused rabbit hearts, the LV was instrumented with a fluid-filled balloon. Increasing volume and pressure pulses were applied at different times of the cardiac cycle. Monophasic action potentials (MAPs) were recorded simultaneously from five LV epicardial sites. Inter-site dispersion of repolarization was calculated in the time and voltage domains.
Results: Sudden balloon inflation induced VF when pressure pulses of 208–289 mmHg were applied within a window of 35–88 msec after MAP upstroke, a period of intrinsic increase in repolarization dispersion. During the pressure pulse, MAPs revealed an additional increase in repolarization dispersion (time domain) by 9 ± 6 msec (P < 0.01). The maximal difference in repolarization levels (voltage domain) between sites increased from 19 ± 3% to 26 ± 3% (P < 0.05). Earliest stretch-induced activation was observed near a site with early repolarization, while sites with late repolarization showed delayed activation.
Conclusions: Sudden myocardial stretch can elicit VF when it occurs during a vulnerable window that is based on repolarization inhomogeneity. Stretch pulses applied during this vulnerable window can lead to nonuniform activation. Repolarization dispersion might play a crucial role in the occurrence of fatal tachyarrhythmias during commotio cordis.