Electrophysiological effects of acute dilatation in the isolated rabbit heart: cycle length-dependent effects on ventricular refractoriness and conduction velocity

BACKGROUND: Acute ventricular dilatation has important electrophysiological effects: Dilatation shortens action potential duration and refractoriness without an apparent effect on conduction velocity. These effects have been implicated as a potential mechanism of arrhythmias in patients with congestive failure. Because the influence of cycle length on these phenomena has not been studied, we examined the effects of dilatation during ventricular pacing at cycle lengths from 1000 to 150 ms. METHODS AND RESULTS: Thin epicardial layers were created in isolated, perfused rabbit left ventricles (n=7). A fluid filled latex balloon was secured in the left ventricle to dilate the left ventricle. Mapping was performed with 248 epicardial electrodes. Longitudinal conduction velocity (76+/-1 cm/s; mean+/-SEM) and transverse conduction velocity (26+/-1 cm/s) were not influenced by dilatation at any cycle length. In contrast, the effects of dilatation in decreasing left ventricular effective refractory period (ERP) were significantly greater at shorter drive cycle lengths: The decrease in ERP was 2+/-2 ms (a 1% change) at a drive cycle length of 1000 ms and 18+/-4 ms (a 20% change) at a drive cycle length of 150 ms. In 10 additional intact, isolated perfused rabbit hearts, dilatation decreased ERP to a greater degree during 250 ms drive cycle length pacing than during pacing at 400 ms (25+/-4 versus 16+/-3 ms; P=.01). CONCLUSIONS: Acute dilatation exaggerates the normal rate-dependent shortening of refractoriness but does not influence transverse or longitudinal conduction velocity. This observation suggests that the electrophysiological effects of acute dilatation may be greater during tachycardia than at slower cycle lengths. This may have implications for arrhythmias in patients with congestive heart failure.     

Pharmacological analysis in rat of the role of the ATP-sensitive potassium channel as a potential target for antifibrillatory intervention in acute myocardial ischaemia

We tested the hypothesis that blockade of the ATP-sensitive K+ channel (IK(ATP)) is an antiarrhythmic mechanism in acute myocardial ischaemia, using an opener of the channel (10 microM RP 49356, RP) and a blocker of the channel (10 microM glibenclamide, GL) and a combination of the two drugs (GL+RP, 10 microM each) in a randomised blinded study. Isolated rat hearts (n = 8 per group) were subjected to 30-min left regional ischaemia. GL and GL+RP widened QT interval after 10-min ischaemia (197 +/- 39 and 203 +/- 20 ms, respectively vs. 154 +/- 12 ms in controls), whereas RP significantly shortened QT interval (123 +/- 6 ms). GL and GL+RP decreased coronary flow (p < 0.05). RP caused slight increase in flow during ischaemia. These effects are all consistent with modulation of vascular and cardiac IK(ATP). RP alone had no effect on ischaemia-induced arrhythmias. Neither did GL have any effect on the incidence of ventricular fibrillation (VF: 88 vs. 100% in controls). However, GL reduced the incidence of sustained VF (VF lasting continuously for > 2 min) to 14% vs. 88% in controls (p < 0.05). Therefore, GL had defibrillatory activity. Surprisingly, in view of these findings, the GL+RP combination significantly reduced the incidence of VF to 25% (from 100% in control hearts, p < 0.05) i.e., had an antifibrillatory effect. So, two agents that produce pharmacological effects attributable to block and opening of IK(ATP) when administered singly had no effects on the incidence of ischaemia-induced VF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnostic criteria for Non-ABCDE hepatitis

1. In the last decade, a number of clinical observations have questioned the efficacy of certain class I antiarrhythmic drugs against ischaemia-induced ventricular fibrillation. The effects of three drugs of this class, disopyramide (Ia), lignocaine (Ib) and flecainide (Ic) on the vulnerability to fibrillation during experimental ischaemia were investigated. 2. The study was carried out in anaesthetized, open-chest pigs (n = 8 for each of the drugs, in addition to the control group, n = 6). Vulnerability to fibrillation was evaluated by measuring electrical fibrillation threshold (EFT) by means of stepwise increased intensity of wide (100 ms) diastolic impulses applied to the ischaemic tissue at a 180 beats min-1 rate. Monophasic action potential (MAP) duration and conduction time in the ischaemic region were also measured. 3. EFT determinations were performed before and during periods of ischaemia induced by complete occlusion of the left anterior descending coronary artery near its origin. Ischaemic periods of increasing duration (30, 60, 90, 120, 150 s) were induced to determine the electrophysiological changes, of EFT especially, leading to fibrillation. 4. In the absence of ischaemia, all three drugs, administered by intravenous route (1 mg kg-1 plus 0.04 mg kg-1 min-1) increased EFT to a similar extent (from approximately 7 to 10 mA), despite a 25% prolongation of conduction time. 5. During ischaemia, none of the drugs prevented the fall in EFT towards 0 mA, resulting in spontaneous fibrillation. After 30 s of ischaemia, they no longer had any capacity for raising EFT and, after 60, 90 and 120 s of ischaemia, the decrease in EFT was exacerbated. This accelerated reduction in EFT shortened the time to onset of fibrillation (after 120 s of ischaemia, 62.5% of fibrillations with flecainide instead of 12.5 under control conditions, 75% instead of 25 with lignocaine and 50% instead of 25 with disopyramide). The reduction in MAP duration due to ischaemia was also significantly accelerated (at 60 s, 178 +/- 5 ms instead of 192 +/- 4 with flecainide, 175 +/- 3 ms instead of 194 +/- 5 with lignocaine and 180 +/- 5 ms instead of 196 +/- 3 with disopyramide) and the slowing of conduction was made worse (prolongation of conduction time by 70% instead of 50). 6. In conclusion, the antifibrillatory properties normally manifested by these drugs are first suppressed, then inverted by ischaemia, depending on oxygen debt varying with severity and duration of ischaemia.     

Actions of halothane and isoflurane on Purkinje fibers in the infarcted canine heart: conduction, regional refractoriness, and reentry

The actions of halothane (HAL) and isoflurane (ISO) on conduction and regional refractoriness were studied in infarcted canine hearts to compare their effects on reentry in vitro. In two anesthetic groups of 8 hearts, high and low dose effects were assessed using action potentials recorded from Purkinje fibers located in the nonischemic and ischemic regions. An extrastimulus technique was used to determine the relationship between delay of conduction of premature impulses into the more refractory ischemic region and induction of reentrant responses. At high doses (HAL 0.60 mM and ISO 0.64 mM, approximately 2.3 minimum alveolar anesthetic concentration [MAC]) both anesthetics decreased (P < or = 0.05) the effective refractory period for direct intracellular stimulation of nonischemic fibers (local ERP, initial control: 294 +/- 8 ms); the decrease with HAL (-29 +/- 6 ms) was smaller (P < or = 0.05) than with ISO (-50 +/- 7 ms). HAL and ISO also decreased (P < or = 0.05) the coupling interval of the earliest premature impulse which conducted into the infarct (system effective refractory period [SERP], control: 301 +/- 7 ms) by -31 +/- 11 and -44 +/- 8 ms, respectively. In contrast, the functional refractory period (FRP) in the ischemic region (control:354 +/- 4 ms) was increased by HAL (26 +/- 8 ms; P < or = 0.05) but decreased by ISO (-14 +/- 4 ms, P < or = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of high intensity drive train stimulation on dispersion of atrial refractoriness: role of autonomic nervous system

OBJECTIVES: This study evaluated the effect of high intensity drive train (S1) stimulation on the atrial effective refractory period (ERP) and its relation to the autonomic nervous system. BACKGROUND: High intensity S1 stimulation was demonstrated to shorten the ventricular ERP and to increase dispersion of refractoriness. These effects may be due to local release of neurotransmitters. The response of the atrium and ventricle to neurotransmitters was different. The effects of high intensity S1 stimulation at the atrial tissue were evaluated. METHODS: Forty patients without structural heart disease were studied. In group 1, 20 patients, the atrial ERP was measured at 0, 7, 14, 21 and 28 mm away from the S1 site under both twice diastolic threshold and high intensity (10 mA) S1 stimulation. The same protocol was repeated after sequential administration of propranolol (0.2 mg/kg body weight) and atropine (0.04 mg/kg). In group 2, the other 20 patients, the atrial ERP was studied at three atrial sites (high lateral right atrium [HLRA], right posterior interatrial septum [RPS] and distal coronary sinus [DCS] with twice diastolic threshold and high intensity S1 stimulation at baseline and after sequential autonomic blockade. The three atrial sites were randomly assigned as the S1 location. RESULTS: In group 1, high intensity S1 stimulation shortened the atrial effective refractory period most prominently at the site of S1: (mean +/- SD) 13.3 +/- 6.4% (p < 0.001), 8.1 +/- 3.8% (p < 0.001), 4.8 +/- 4.3% (p < 0.001), 3.7 +/- 4.7% (p < 0.001) and 0.5 +/- 2.6% at 0, 7, 14, 21 and 28 mm from the S1 site, respectively. The effect of high intensity S1 stimulation was blunted with propranolol and autonomic blockade but persisted after atropine alone. High intensity S1 stimulation also increased dispersion of refractoriness (from 23 +/- 11 ms to 31 +/- 12 ms, p = 0.01), which was eliminated with autonomic blockade. In group 2, high intensity S1 stimulation had similar effects at different locations (ERP shortening of 10.8 +/- 2.7%, 10.8 +/- 2.2% and 12.2 +/- 4.6% at the HLRA, RPS and DCS, respectively). The responses to sequential autonomic blockade were similar to those in group 1. However, high intensity S1 stimulation at HLRA increased dispersion of refractoriness, but at DCS it reduced dispersion of refractoriness. CONCLUSIONS: High intensity S1 stimulation led to local shortening of the atrial ERP and increased dispersion of refractoriness. These effects were blunted with propranolol and autonomic blockade. High intensity S1 stimulation at the HLRA increased dispersion of atrial refractoriness, whereas the same stimulation at the DCS decreased dispersion of atrial refractoriness.     

Dispersion of ventricular repolarization in left ventricular hypertrophy: influence of afterload and dofetilide

INTRODUCTION: Increased dispersion of ventricular repolarization is observed in cardiac hypertrophy and is associated with sudden cardiac death. At present, there is little information about the effects of cardiac hemodynamics and antiarrhythmic drugs on dispersion of repolarization in disease states. We compared the effects of increasing afterload and the Class III antiarrhythmic drug, dofetilide, on dispersion of ventricular repolarization in hypertrophied rabbit hearts to normal rabbit hearts. METHODS AND RESULTS: Cardiac hypertrophy was induced in rabbits by abdominal aortic banding. Isolated hearts were studied 49+/-4 days postsurgery in the working heart mode using a blood-buffer perfusate. The action potential duration (APD) was measured from eight sites on the epicardium of the heart at low (50+/-7 mmHg) afterload and high afterload (97+/-12 mmHg) at baseline and during dofetilide perfusion. APD dispersion, determined as the difference between the maximal and minimal APD, was greater in hypertrophied hearts (42+/-8 msec) compared with control hearts (26+/-8 msec, P < 0.05) at baseline and low afterload. Increasing afterload caused a decrease in APD dispersion in hypertrophied hearts (P < 0.05) but not in control hearts, and APD dispersion was similar in hypertrophied hearts (31+/-9 msec) compared with control hearts (30+/-9 msec, P = NS). During dofetilide perfusion, APD dispersion remained greater in hypertrophied hearts (60+/-39 msec) compared with control hearts (30+/-13 msec, P < 0.05) at low afterload but not high afterload. Increasing afterload caused shortening of the APD in most regions of the control hearts, whereas APD did not shorten significantly in hypertrophied hearts at baseline and tended to increase during dofetilide perfusion. During dofetilide perfusion, the maximal change in APD recorded from the posterior wall of the left ventricle following an increase in afterload was -18+/-21 msec in control hearts and 7+/-21 ms in hypertrophied hearts (P < 0.05). CONCLUSION: Epicardial APD dispersion decreases in hypertrophied hearts following an increase in afterload, and this response is mediated in part by the absence of afterload-induced shortening of the APD. This effect may be due in part to altered responses of the delayed rectifying current to cardiac loading conditions in the setting of cardiac hypertrophy.     

Effects of ketamine on ventricular conduction, refractoriness, and wavelength: potential antiarrhythmic effects: a high-resolution epicardial mapping in rabbit hearts

BACKGROUND: The aims of the study were to verify the effects of ketamine on ventricular conduction velocity and on the ventricular effective refractory period, to determine its effects on anisotropy and on homogeneity of refractoriness, and to use wavelength to determine whether ketamine has antiarrhythmic or arrhythmogenic properties. METHODS: A high-resolution epicardial mapping system was used to study the effects of 50, 100, 150, and 200 microM racemic ketamine in 15 isolated, Langendorff-perfused rabbit hearts. Five hearts were kept intact to study the effects of ketamine on spontaneous sinus cycle length (RR) interval and its putative arrhythmogenic effects. In 10 other hearts, a thin epicardial layer was obtained by an endocardial cryoprocedure (frozen hearts) to study ventricular conduction velocity, ventricular effective refractory periods (five sites), and ventricular wavelength. RESULTS: Ketamine induced a concentration-dependent lengthening of the RR interval. Ketamine slowed longitudinal and transverse ventricular conduction velocity with no anisotropic change, and it prolonged the ventricular effective refractory period with no significant increase in dispersion. Ventricular longitudinal and transverse wavelengths tend to increase, but this was not statistically significant. Finally, no arrhythmia could be induced regardless of the ketamine concentration. CONCLUSION: Ketamine slowed ventricular conduction and prolonged refractoriness without changing anisotropy or increasing dispersion of refractoriness. Although these effects should result in significant antiarrhythmic effects of ketamine, this should not be construed to suggest a protective effect in ischemic or other abnormal myocardium.     

Tachycardia-induced change of atrial refractory period in humans: rate dependency and effects of antiarrhythmic drugs

BACKGROUND: Atrial fibrillation (AF) has been shown to shorten the atrial effective refractory period (ERP) and make the atrium more vulnerable to AF. This study investigated the effect of atrial rate and antiarrhythmic drugs on ERP shortening induced by tachycardia. METHODS AND RESULTS: Seventy adult patients without structural heart disease were included. For the first part of the study, right atrial ERP was measured with a drive cycle length of 500 ms before and after 10 minutes of rapid atrial pacing using five pacing cycle lengths (450, 400, 350, 300, and 250 ms) in 10 patients. For the second part of the study, the remaining 60 patients were included to study the effects of antiarrhythmic drugs on changes in atrial ERP induced by AF. Atrial ERP was measured with a drive cycle of 500 ms before and after an episode of pacing-induced AF. After the patients were randomized to receive one of six antiarrhythmic drugs (procainamide, propafenone, propranolol, dl-sotalol, amiodarone, and verapamil), atrial ERP was measured before and after another episode of pacing-induced AF. In the first part of the study, atrial ERP shortened significantly after 10 minutes of rapid atrial pacing, and the degree of shortening was correlated with pacing cycle length. The second part of the study showed that atrial ERP shortened after conversion of AF (172+/-15 versus 202+/-14 ms, P<0.0001) and that ERP shortening was attenuated after verapamil infusion (-4.6+/-1.2% versus -15.1+/-3.4%, P<0.001) but was unchanged after infusion of the other antiarrhythmic drugs. Furthermore, all of these antiarrhythmic drugs could decrease the incidence and duration of secondary AF. CONCLUSIONS: The atrial ERP shortening induced by tachycardia was a rate-dependent response. Verapamil, but not other antiarrhythmic drugs, could markedly attenuate this effect. However, verapamil and the other drugs could decrease the incidence and duration of secondary AF.     

Comparison of direct negative chronotropic and positive inotropic effects of sematilide to those of E-4031 and MS-551 and the reverse frequency-dependent prolongation of cardiac refractoriness of sematilide

Direct cardiac effects of sematilide, a new class III antiarrhythmic drug, were compared with those of E-4031 and MS-551 in canine isolated blood-perfused heart preparations. Doses of sematilide, E-4031, and MS-551 causing a 10% decrease in the spontaneous sinoatrial beating rate were 58 +/- 15, 9 +/- 5, and 84 +/- 10 micrograms (n = 5); those causing a 10% increase in developed tension of the papillary muscle were 485 +/- 49, 17 +/- 2, and 267 +/- 50 micrograms (n = 6); and those causing a 10% prolongation of effective refractory period (ERP) of the atrioventricular node were 68 +/- 10, 11 +/- 2, and 53 +/- 15 micrograms (n = 5), respectively. There were few effects on atrio-His or His-ventricular intervals. Also, in in situ open-chest dog hearts, the percent increases in ERP of the atrioventricular conduction system caused by 1 mg/kg of sematilide were 21 +/- 3, 16 +/- 2 and 9 +/- 1% at cycle lengths of 800, 600, and 400 ms, respectively (p < 0.01; n = 8). These results indicate that (a) sematilide, as well as E-4031 and MS-551, has direct negative chronotropic and positive inotropic effects and prolongs cardiac refractoriness without affecting conduction velocities; (b) quantitatively, the cardiac effects of sematilide were almost identical to those of MS-551 and five to ten times less potent than those of E-4031; (c) and prolongation of ERP of the atrioventricular conduction system by sematilide occurred in a reverse frequency-dependent manner.     

Generalized peroxisomal disorder in male twins: fatty acid composition of serum lipids and response to n-3 fatty acids

Ischemia leads to intracellular acidification which can be counteracted by the Na+/H+-exchange mechanism. A blockade of this exchanger has been hypothesized to cause stronger intracellular acidification in the course of ischemia thereby protecting the heart from ischemic damage. The aim of our study was to find out (1) whether in the course of ischemia areas become electrically silent, (2) whether this is enhanced by the Na+/H+-exchange inhibitor cariporide (4-Isopropyl-3-methylsulfonylbenzoyl-guanidine; Hoe 642) and whether cariporide has protective effects. Therefore, we submitted isolated rabbit hearts, perfused according to the Langendorff technique to regional ischemia (LAD occlusion) for 30 min followed by 30 min reperfusion with (n=7) or without (n=7) pre-treatment with 1 microM cariporide. Under these conditions 256-channel epicardial potential mapping was carried out. Under non-ischemic conditions cariporide did not alter any of the parameters under observation. We found that ischemia led to marked alterations of the activation pattern, to action potential shortening and a marked increase in the dispersion of refractoriness. In the ischemic region there was a significant ST deviation from the isoelectrical line (control 32+/-10; 30 min ischemia: 290+/-35 arbitrary units [a.u.]). This was markedly reduced by cariporide (control 39+/-10; 30 min ischemia: 170+/-25 a.u.). The increase in dispersion by ischemia (by 50+/-5 ms) was significantly counteracted by cariporide (increased dispersion by 20+/-4 ms). In a similar way the alteration of the activation pattern was antagonized. Under the influence of cariporide we found a lower increase in the left ventricular enddiastolic pressure, and a significantly slower recovery of the action potential duration. After 30 min of ischemia 24+/-5 (control series) 24.5+/-5 mm2 (cariporide) became electrically silent. In a second series of experiments the incidence of arrhythmia was assessed: we found ventricular fibrillation in 6/7 untreated control hearts and in 4/7 cariporide treated hearts. In a third series of experiments we determined the intracellular [ATP] after 30 min of LAD occlusion using a histochemical method. We observed a decrease in [ATP] in the ischemic region as compared to the non-ischemic right ventricular wall, which was less pronounced in cariporide-treated hearts. Thus, we conclude that (1) cariporide protects the heart from ischemic damage and (2) at least under these conditions an enlargement of the electrically silent area did not occur.     

Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry

OBJECTIVE: Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. METHODS: Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation-recovery intervals (ARI). RESULTS: Under S (9.9-14.5 mg.l-1), spontaneously terminating PVTs (cycle length of 270 +/- 43 ms, n = 45) (mean +/- s.d.) occurred when a PE bolus (10-50 micrograms.kg-1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295 +/- 47 ms) were significantly prolonged prior to PVT (462 +/- 92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to > 500 ms). Maximum delays > 200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. CONCLUSION: Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.     

Frequency-dependent effects of propafenone decrease with duration of ventricular tachycardia in isolated guinea pig hearts

Na+ channel blockers terminate tachyarrhythmias primarily by rate-dependent effects. The purpose of this study was to investigate the use-dependent effects of propafenone in isolated guinea pig and rabbit hearts perfused by the method of Langendorff. In the presence of propafenone (0.3 microM) during ventricular pacing, an abrupt decrease of the pacing cycle length (220 ms to 120 ms) slowed the intraventricular conduction with a transient peak QRS prolongation of 33.8 +/- 2.0% after 5.7 +/- 0.5 s (P < 0.01) which subsequently decreased to a steady state of 14.0 +/- 2.5% after 38.0 +/- 5.5 s (mean +/- S.E.M.; n = 10; P < 0.01). The ventricular effective refractory period was significantly prolonged if evaluated by a train of 10 basic stimuli (S1) (interstimulus interval: 120 ms) followed by a premature stimulus (S2). However, when the train of basic stimuli was increased the effective refractory period diminished progressively. An initial increase in total activation time vanished with continued rapid ventricular stimulation. These effects may be explained by a shortening of the action potential during high rates resulting in a decreased binding of propafenone to Na+ channels.     

Effect of flecainide on atrial and ventricular refractoriness and conduction in patients with normal left ventricle. Implications for possible antiarrhythmic and proarrhythmic mechanisms

We studied the effects of intravenous flecainide (2 mg.kg-1) on atrial and ventricular refractoriness and conduction during sinus rhythm, induced atrial fibrillation and atrial pacing at rates of 100, 120 and 150 ppm, in 14 patients with normal left ventricle. Flecainide caused a significant increase in QRS duration during sinus rhythm (mean +/- SD: 87.2 +/- 8.4 ms vs 102.8 +/- 9.1 ms, P < 0.001), atrial fibrillation (87.8 +/- 10.0 ms vs 108.8 +/- 13.7 ms, P < 0.001) and at all paced rates. The duration of the atrial electrogram was significantly increased during sinus rhythm (54.9 +/- 13.2 ms vs 64.8 +/- 16.6 ms, P = 0.003) and at all pacing rates. The PA interval was also significantly prolonged, as was the pacing stimulus-to-atrial-electrogram interval at all pacing rates. There was increased QRS duration and atrial electrogram prolongation at higher pacing rates. Atrial refractoriness was prolonged during sinus rhythm (216.4 +/- 28.2 vs 228.6 +/- 36.1, P = 0.02), but not during atrial pacing at any rate. The QT interval, but not the JT interval or ventricular refractoriness, was significantly prolonged during sinus rhythm and at all pacing rates. Flecainide slows atrial conduction in a use dependent manner and increases atrial refractoriness during sinus rhythm but not during faster atrial pacing, thus not displaying a use-dependent effect. QRS duration is prolonged in a use-dependent manner without a commensurate increase in ventricular refractoriness. In the presence of rapidly conducted atrial fibrillation, which was not found to be slowed by flecainide, this effect may constitute a proarrhythmic mechanism even in patients with no apparent myocardial abnormality.     

Amiodarone reduces transmural heterogeneity of repolarization in the human heart

OBJECTIVES: The present work was designed to test the effects of amiodarone therapy on action potential characteristics of the three cell types observed in human left ventricular preparations. BACKGROUND: The electrophysiologic basis for amiodarone's exceptional antiarrhythmic efficacy and low proarrhythmic profile remains unclear. METHODS: We used standard microelectrode techniques to investigate the effects of chronic amiodarone therapy on transmembrane activity of the three predominant cellular subtypes (epicardial, midmyocardial [M] and endocardial cells) spanning the human left ventricle in hearts explanted from normal, heart failure and amiodarone-treated heart failure patients. RESULTS: Tissues isolated from the ventricles of heart failure patients receiving chronic amiodarone therapy displayed M cell action potential duration (404+/-12 ms) significantly briefer (p < 0.05) than that recorded in tissues isolated from normal hearts (439+/-22 ms) or from heart failure patients not treated with amiodarone (449+/-18 ms). Endocardial cells from amiodarone-treated heart failure patients displayed longer (p < 0.05) action potential duration (363+/-10 ms) than endocardial cells isolated from normal hearts (330+/-6 ms). As a consequence, the heterogeneity of ventricular repolarization in tissues from patients treated with amiodarone was considerably smaller than in the two other groups, especially at long pacing cycle lengths. CONCLUSIONS: These findings may explain, at least in part, the reduction of ventricular repolarization dispersion and the lower incidence of torsade de pointes observed with chronic amiodarone therapy as compared with other class III agents.     

International Symposium on the Role of HDL in Disease Prevention: report on a meeting

An area of unidirectional conduction block is one requirement for reentrant arrhythmias to occur. Functional block caused by dispersion of repolarization and refractoriness is the most probable mechanism of drug-induced unidirectional conduction block. We assessed the effects of lidocaine on spatial dispersion of myocardial repolarization and refractoriness in the intact porcine heart. Monophasic action potential duration at 90% repolarization, effective refractory period (ERP), and ventricular fibrillation cycle length (VFCL) were measured at two endocardial and one epicardial sites at baseline and during a treatment phase with D5W (n=11) or lidocaine 10 mg/kg/hour (n=12). Dispersion was calculated as the difference between the maximum and minimum values of the three recording sites. Lidocaine produced significant changes in ERP, VFCL, paced QRS duration, and intraventricular conduction time. It did not change basal levels of dispersion in repolarization and refractoriness. Lidocaine produced changes in myocardial electrophysiology that are uniform across the myocardium and thus did not change myocardial electrical heterogeneity. This may be a mechanism of the agent's lower proarrhythmic effects compared with other sodium channel blockers that increase myocardial electrical heterogeneity.     

Effect of coronary angioplasty on precordial QT dispersion

Dispersion of the QT interval is a measure of inhomogeneity of ventricular repolarization. Because ischemia is associated with regional abnormalities of conduction and repolarization, we hypothesized that the surface electrocardiographic interval dispersion would increase in patients with symptomatic coronary artery disease in the absence of myocardial infarction and that successful revascularization would reduce QT interval dispersion. Thirty-seven consecutive patients with ischemia due to 1-vessel coronary artery disease without prior myocardial infarction who underwent percutaneous transluminal coronary angioplasty (PTCA) were evaluated. Standard 12-lead electrocardiograms were performed 24 hours before, 24 hours after, and late (>2 months) after PTCA. Precordial QT interval dispersions were determined from differences in the maximum and minimum corrected QT intervals. Mean QT interval dispersion before PTCA was 60 +/- 9 ms, immediately after PTCA 23 +/- 14 ms (p <0.001), and late after PTCA 29 +/- 18 ms (p <0.001 vs before PTCA). The shortest precordial QT interval increased immediately after PTCA (367 +/- 40 vs 391 +/- 39 ms; p <0.02) and then remained stable late after PTCA (376 +/- 36 ms, p = NS vs immediately after PTCA). Symptomatic recurrent ischemia in 8 patients with documented restenosis increased QT interval dispersion (56 +/- 15 ms [p <0.01] vs 25 +/- 14 ms immediately after PTCA), which decreased again after successful repeat PTCA (22 +/- 13 ms [p <0.01] vs before the second PTCA). QT interval dispersion decreases after successful coronary artery revascularization and increases with restenosis. Therefore, QT interval dispersion may be a marker of recurrent ischemia due to restenosis after PTCA.     

Activation-repolarization coupling in the normal swine endocardium

BACKGROUND: While abnormalities of activation and repolarization play an important role in arrhythmogenesis, little information is available on the interaction between their spatial dispersions in the heart. This study examined the effects of activation spread on the spatial distribution of the repolarization properties during different depolarization patterns. METHODS AND RESULTS: Left ventricular (LV) endocardial activation and repolarization patterns were mapped in 13 healthy pigs. LV local activation, repolarization, and activation-recovery interval (ARI) times were determined from the intracardiac unipolar electrograms, color-coded, and superimposed on a three-dimensional anatomic map of the ventricle generated with a nonfluoroscopic mapping system. ARI values correlated with the duration of monophasic activation potential recorded from onset of activation to time of 90% repolarization (r=.97, P<.01). Activation time range of the left ventricle was 42+/-5 ms (mean+/-SEM) during sinus rhythm and 54+/-5 ms during right ventricular septal pacing. ARI inversely correlated with the corresponding activation times during both sinus (r2=.76+/-.03) and paced (r2=.77+/-.02) rhythms. The longest ARIs were located at the sites of earliest activation and shortest at the latest activation areas, with gradual shortening between them. CONCLUSIONS: The spatial distribution of repolarization is dependent on the activation pattern. Repolarization dispersion in the healthy swine heart is relatively small as the result of tight coupling of the action potential duration to the activation process, assigning longer ARIs to sites activated earlier. This coupling reduces global and regional dispersion of repolarization and may serve as an important antiarrhythmic mechanism present in normal myocardium.     

Concerning the effect of the K+ channel blocking agent glibenclamide on ischaemic and reperfusion arrhythmias

Reports on effects of ATP-dependent K+ channel modulating drugs on ischaemia-induced cardiac arrhythmias have been scarce and contradictory. The channel blocking agent glibenclamide (glyburide) has been considered as an antiarrhythmic candidate, because it antagonizes the ischaemic K+ efflux and the shortening of the refractory period. In the present investigation its effects were tested, therefore, in rat hearts with coronary occlusion and reperfusion. In untreated hearts, tachyarrhythmias occurred during the reperfusion, and less pronounced during the coronary occlusion itself. Large amounts of adenosine and its degradation products were released during the coronary reperfusion, particularly from hearts which developed ventricular fibrillation. Glibenclamide (0.1 and 1.0 micromol/l perfusion fluid) neither antagonized the ischaemic nor the reperfusion arrhythmias. Ischaemic arrhythmias were even intensified. Also in control hearts without coronary occlusion, pro-arrhythmic effects of glibenclamide were observed. Furthermore, the coronary flow was considerably decreased by the drug, and the release of adenosine and its metabolites was significantly increased. Sodium nitroprusside antagonized the glibenclamide-induced decrease in the coronary flow, but did not prevent the arrhythmias. The Ca2+ channel blocking agent gallopamil increased the coronary flow, decreased the adenosine release, and antagonized the arrhythmias in hearts with and without glibenclamide. In conclusion, the present findings do not favour the idea of an antiarrhythmic effect of glibenclamide. Rather, some propensity to the occurrence of arrhythmias can be produced by the drug.     

Hoe 694, a new Na+/H+ exchange inhibitor and its effects in cardiac ischaemia

1. The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4- piperidino-benzoyl) guanidine methanesulphonate) was characterized as an inhibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bovine endothelial cells. The potency of the compound was slightly lower or comparable to ethylisopropyl amiloride (EIPA). 2. To investigate a possible cardioprotective role of the Na+/H+ exchange inhibitor Hoe 694, rat isolated working hearts were subjected to ischaemia and reperfusion. In these experiments all untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 10(-7) M Hoe 694 to the perfusate almost abolished reperfusion arrhythmias in the rat isolated working hearts. 3. Hoe 694 reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), which are indicators of cellular damage during ischaemia, into the venous effluent of the hearts by 60% and 54%, respectively. 4. The tissue content of glycogen at the end of the experiments was increased by 60% and the high energy phosphates ATP and creatine phosphate were increased by 240% and 270% respectively in the treated hearts as compared to control hearts. 5. Antiischaemic effects of the Na+/H+ exchange inhibitor, Hoe 694, were investigated in a second experiment in anaesthetized rats undergoing coronary artery ligation. In these animals, pretreatment with Hoe 694 caused a dose-dependent reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation down to doses of 0.1 mg kg-1, i.v. Blood pressure and heart rate remained unchanged. 6. We conclude that the new Na+/H+ exchange inhibitor, Hoe 694, shows cardioprotective and antiarrhythmic effects in ischaemia and reperfusion in rat isolated hearts and in anaesthetized rats. In view of the role which Na+/H+ exchange seems to play in the pathophysiology of cardiac ischaemia these effects could probably be attributed to Na+/H+ exchange inhibition.     

Electrophysiological characteristics of the human atria after cardioversion of persistent atrial fibrillation

BACKGROUND: In animal models, induced atrial fibrillation shortens the atrial effective refractory period (ERP) and reverses its physiological adaptation to rate. It is not clear whether this process, known as "electrical remodeling," occurs in humans. METHODS AND RESULTS: We determined the ERPs, at 5 pacing cycle lengths (300 to 700 ms) and in 5 right atrial sites, after internal cardioversion of chronic atrial fibrillation in 25 patients (14 in pharmacological washout and 11 on amiodarone). The ERPs were 195.5+/-18.8 ms in the washout and 206.3+/-17.9 ms in the amiodarone patients (P<0.0001). ERPs were closely correlated with the stimulation rates (r=0.95 in the washout and r=0.94 in the amiodarone group), and slope values indicating a normal (>/=0.07) or nearly normal (0.05 to 0.06) adaptation of ERP to rate were found in 77% of the 84 paced sites. The mean ERP was shorter in the lateral wall (198.1+/-17.9 ms) than in the atrial roof (203.3+/-21.5 ms) and in the septum (210.5+/-20.0 ms) (P<0.03). After 4 weeks of sinus rhythm, the mean ERP, determined again in 8 patients (4 in wash-out and 4 on amiodarone), was significantly increased compared with the basal study (221. 4+/-21.4 versus 197.8+/-18.3 ms, P<0.0001). CONCLUSIONS: After cardioversion of chronic atrial fibrillation, (1) atrial ERP adaptation to rate was normal or nearly normal in the majority of the cases, (2) a significant dispersion of refractoriness between different right atrial sites was present, and (3) ERPs were significantly increased after 4 weeks of sinus rhythm in both washout and amiodarone patients.