Functional Refractory Period Research Articles

Actions of Halothane and Isoflurane on Purkinje Fibers in the Infarcted Canine Heart

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)

Radiofrequency versus pharmacologic modification of the atrioventricular node

Although transcatheter radiofrequency modification of the atrioventricular (AV) node has been proposed as curative treatment in AV nodal reentry tachycardias, its role for the control of the ventricular rate in atrial tachyarrhythmias remains unclear. The aim of this study was to analyze the acute effect of radiofrequency current on AV nodal conduction and refractoriness, and to compare it with the effects of two antiarrhythmic drugs such as amiodarone (class III) and flecainide (class I). Twenty-one dogs were studied: (1) radiofrequency group (5 W for less than 45 seconds; 2 to 12 discharges: seven dogs); (2) amiodarone group (5 mg/kg intravenously; seven dogs); and (3) flecainide group (2 mg/kg intravenously; seven dogs). The following parameters were measured under basal conditions and after each procedure: AH interval, AV nodal functional refractory period, Wenckebach cycle length, minimum R-R interval during atrial fibrillation, and fitting of AV nodal function curve to a hyperbolic equation using its linear transformation. The AV nodal effective refractory period could not be calculated in any dog in the basal study because it was shorter than the atrial functional refractory period. After radiofrequency, the percentage increment was greater for the AH interval than for the AV nodal functional refractory period (60 ± 28% versus 29 ± 16%, p ≤ 0.05); the percentage increment in the AH interval did not correlate with that of any other interval, whereas the percentage increment of the AV nodal functional refractory period correlated with that of the Wenckebach cycle length ( r = 0.83, p ≤ 0.05) and minimum R-R interval during atrial fibrillation ( r = 0.78, p ≤ 0.05). Neither after amiodarone (62 ± 16% versus 50 ± 21%, p = NS) nor after flecainide (18 ± 7% versus 12 ± 6%, p = NS) were there significant differences between the percentage incremento in the AH interval and AV nodal functional refractory period; furthermore, unlike radiofrequency, the percentage increment in the AH interval correlated with that of the AV nodal functional refractory period after amiodarone ( r = 0.87, p ≤ 0.01) and flecainide ( r = 0.86, p ≤ 0.01). The AV nodal function curve was displaced upwards and to the right with each procedure; the ordinate axis intercept of the straight line of the hyperbolic equation significantly decreased only with amiodarone. It was concluded that: (1) Radiofrequency current, unlike antiarrhythmic drugs, induces a dissociation between conduction and refractoriness, with a predominant modification of the former. (2) The prolongation of the parameters valuable in controlling ventricular rate in atrial tachyarrhythmias (Wenckeback cycle length and minimum R-R interval during atrial fibrillation) depends on the modification of AV nodal refractoriness and not on the increase in the AH interval. (3) The prolongation of the AH interval can be a misleading end point during the ablation procedures.

Differential effects of isoproterenol on sustained ventricular tachycardia before and during procainamide and quinidine antiarrhythmic drug therapy.

Autonomic modulation, especially increased sympathetic activity may play a role in the genesis of ventricular arrhythmias. The purpose of this study was to determine whether beta-sympathetic stimulation with isoproterenol would alter sustained ventricular tachycardia (VT) circuits similarly during the drug-free and antiarrhythmic drug-treated states. Twenty-five patients with repeatedly inducible, hemodynamically stable, sustained VT were evaluated by programmed ventricular stimulation. In the antiarrhythmic drug-free state, isoproterenol (0.03 microgram/kg per minute) shortened the following intervals (in milliseconds; mean +/- SEM; 25 patients; paired t test): sinus cycle length (792 +/- 37 to 568 +/- 18; (p < 0.001), ventricular paced QT interval (386 +/- 8 to 348 +/- 6; p < 0.001), ventricular paced QRS duration (185 +/- 4 to 182 +/- 4; p = 0.014), ventricular effective (238 +/- 5 to 208 +/- 4; p < 0.001) and functional (261 +/- 6 to 227 +/- 5; p < 0.001) refractory periods, and the VT cycle length (VTCL) (311 +/- 9 to 291 +/- 9; p < 0.001). Isoproterenol (0.03 microgram/kg per minute) was administered during 31 antiarrhythmic drug trials (procainamide, n = 18; quinidine, n = 13) in 22 patients. Isoproterenol shortened the sinus cycle length, QT interval during ventricular pacing, and ventricular effective and functional refractory periods before and during procainamide and quinidine therapy (ANOVA; isoproterenol effect, p < or = 0.0002 for all). The amount of decrease in these intervals with isoproterenol was the same before and during procainamide and quinidine therapy (ANOVA interaction, p = NS for all). The QRS duration during ventricular pacing and VTCL were also shortened by isoproterenol before and during procainamide (baseline, n = 17; QRS, 182 +/- 4 to 178 +/- 4 msec; VTCL, n = 18, 314 +/- 11 to 291 +/- 11 msec; during procainamide, QRS, 218 +/- 7 to 197 +/- 6 msec; VTCL, 422 +/- 15 to 359 +/- 11 msec) and quinidine (baseline, n = 13; QRS, 190 +/- 6 to 185 +/- 5 msec; VTCL, n = 12, 298 +/- 10 to 280 +/- 9 msec; during quinidine, QRS, 223 +/- 9 to 208 +/- 8 msec; VTCL, 415 +/- 14 to 355 +/- 10 msec) (isoproterenol effect p < or = 0.0003 for all). However, the amount of decrease in QRS duration and VTCL with isoproterenol was greater during procainamide and quinidine than in the drug-free state (ANOVA interaction, p < or = 0.02 for all). These changes continued to be significant when normalized for the initial QRS duration and VTCL (p < or = 0.03 for all). Isoproterenol affects presumed reentrant sustained VT circuits less in the absence of antiarrhythmic drugs but markedly attenuates the antiarrhythmic drug-induced slowing of sustained VT. To the extent that the change in QRS duration reflects a change in conduction within the VT circuit, these data imply that the attenuation of drug-induced slowing of VT by isoproterenol is due to a greater change in conduction rather than refractoriness.

Initiation of atrial fibrillation in the Wolff-Parkinson-White syndrome: The importance of the accessory pathway

Atrial fibrillation in the Wolff-Parkinson-White syndrome may be related to microreentry in the accessory pathway. If such is the case, catheter ablation of the accessory pathway should eliminate atrial fibrillation. Among 95 patients undergoing catheter ablation, 20 had atrial fibrillation during standard electrophysiologic study (atrial vulnerability) before ablation. There were 16 women and four men with a mean age of 32 years. Before ablation six patients required electrical cardioversion. Thirty minutes after ablation, 11 continued to have inducible atrial fibrillation. Atrial fibrillation terminated spontaneously in every patient after ablation. A control group of 20 patients with accessory pathway ablation had no inducible atrial fibrillation before or after ablation. Catheter ablation had no effect on atrial properties including functional refractory period (227 ± 37 vs 215 ± 29 msec before versus after ablation, mean ± SD) or wavelength (7.4 ± 3.2 vs 7.2 ± 2.7 before versus after ablation). These data suggest that an intact accessory pathway is not necessary for initiation of atrial fibrillation in most patients with Wolff-Parkinson-White syndrome. A rapid ventricular response over the accessory pathway may facilitate the perpetuation of atrial fibrillation in persons prone to this arrhythmia.

Selective elimination of retrograde conduction by intraoperative neodymium: YAG laser photocoagulation in dogs

Objectives. The purpose of this study was to test the feasibility of selective elimination of ventriculoatrial (VA) conduction by limited laser photocoagulation of the atrioventricular (AV) node, and to analyze the histologic substrate of unidirectional retrograde block.Background. Atrioventricular node reentry requires intact retrograde conduction.Methods. Neodymium:yttrium-aluminum-garnet laser photocoagulation was performed during cardiopulmonary bypass through a right atriotomy in 15 dogs that had intact retrograde conduction before operation. Short laser pulses were delivered to an area between the coronary sinus orifice and the proximal His bundle. The end point of lasing was second-degree AV node block at a paced atrial cycle length of 250 ms.Results. Complete retrograde block developed immediately in 11 of the 15 dogs (group I), while AV conduction persisted in all 11. In 4 of the 15 dogs (group II), both AV and VA conduction remained intact. During a 3-month follow-up period, retrograde conduction remained absent in all group I dogs. Retrograde block was not reversed by isoproterenol. Anterograde AV node characteristics (WencKebach cycle length, functional refractory period, ventricular rate during atrial fibrillation) were unchanged in five dogs and modified in six. Complete AV block did not develop. In four control dogs (group III, sham operation), anterograde and retrograde AV node characteristics were unchanged. The anterograde Wenckebach cycle lengths in groups I, II and III at 3 months measured 192 ± 15 ms, 195 ± 6 ms and 170 ± 22 ms, respectively, whereas the retrograde Wenckebach cycle lengths in groups II and III measured 345 ± 62 ms and 278 ± 25 ms, respectively. Histologic study at 3 months in cases with unidirectional VA block showed the compact part of the AV node intact with destruction of the atrial approaches and the superificial layers of the proximal end of the node on the right side.Conclusions. 1) With limited laser photocoagulation of the proximal node area, VA conduction can be eliminated and anterograde AV node transmission maintained. 2) Destruction of the atrial approaches on the right side with preservation of the compact part of the AV node may result in unidirectional retrograde block.

Antiarrhythmic and electrophysiological effects of amiodarone, lignocaine, and penticainide in anaesthetised rats.

The aim was to correlate the relative abilities of amiodarone, lignocaine, and penticainide in suppressing ventricular tachyarrhythmias in response to coronary artery occlusion with their relative abilities to prolong ventricular functional refractory periods and to reduce intraventricular conduction velocities in anaesthetised open chest rats. Functional refractory period was measured with a paired electrical stimulation technique. Intraventricular conduction velocity was monitored using the QRS duration of the ECG. Low doses of these three drugs were selected which protected against ventricular tachyarrhythmias induced by coronary occlusion. These doses prolonged the functional refractory period without increasing QRS duration. High doses of both amiodarone and lignocaine were more effective than low doses in suppressing coronary occlusion induced ventricular tachyarrhythmias. Such high doses greatly prolonged the functional refractory period but prolonged the QRS duration only moderately. In contrast, higher doses of penticainide failed to inhibit coronary occlusion induced ventricular tachyarrhythmias. These higher doses of penticainide prolonged the functional refractory period but prolonged the QRS duration even more markedly. Among these three drugs an increase in functional refractory period appears to be antiarrhythmic. In contrast, widening of the QRS complex without a corresponding increase in functional refractory period, as produced by penticainide, appears to counteract the antiarrhythmic effect.

Dissociation of atrioventricular conduction and refractoriness following application of radiofrequency energy to the canine atrioventricular node: acute and chronic observations.

The electrophysiology of AV nodal modification induced by radiofrequency energy (n = 5) or a sham procedure (n = 5) was studied in ten dogs. The five dogs that received radiofrequency energy had an AH prolongation > 100% from baseline values and this prolongation persisted throughout the 2-month study. The AV nodal functional refractory period was prolonged only acutely. These data indicate a dissociation between the effects on AV nodal conduction and refractoriness that was induced by this procedure. The five sham treated controls showed no acute or chronic electrophysiological changes. In the dogs that received radiofrequency energy, there was fibrosis of the approaches to the AV node and the region of the AV node itself. It is concluded that chronic modification of AV nodal conduction without concomitant changes in refractoriness can be induced by radiofrequency energy delivered in the proximal portion of the AV node. It would be anticipated that this procedure would not decrease the ventricular response to atrial fibrillation or flutter, may be effective in preventing AV nodal reentrant tachycardia by interfering with conduction either in the AV node or perinodal region. Since the AV node itself suffers at least moderate pathological damage, there may be an appreciable incidence of the late development of complete heart block after this procedure.

Beat-to-beat changes in AV nodal refractory and recovery properties during Wenckebach cycles.

The roles of changes in refractory and recovery properties of the atrioventricular node as affected by facilitation and fatigue in the genesis of Wenckebach periodicity were studied in isolated rabbit heart preparations. The contribution of nodal recovery time, facilitation, and fatigue to beat-to-beat changes in nodal conduction time (NCT) and effective (ERPN) and functional refractory periods of node (FRPN) occurring during stable 4:3 Wenckebach cycles was determined with premature stimulation protocols performed during these cycles. Fatigue prolonged, equally for each beat, NCT, ERPN, and FRPN, and therefore did not contribute to Wenckebach periodicity. Beat-to-beat increases in facilitation broadened the range of recovery times for which conduction was successful and decreased NCT, ERPN, and FRPN below the values expected from fatigue alone. However, ERPN and NCT increased overall from beat to beat because of NCT-induced (effects of NCT on ensuing refractoriness) increases in nodal refractoriness and consequent shortenings of the recovery time. These findings establish a complementary role for the recovery and refractory properties in generating the Wenckebach periodicity and demonstrate the modulating roles of facilitation and fatigue on this phenomenon.

Clinical and electrophysiologic effects of intravenous dofetilide (UK-68,798), a new class III antiarrhythmic drug, in patients with angina pectoris

Dofetilide (UK-68,798) is a new class III antiarrhythmic agent. In animal experiments it selectively prolongs the refractory periods parallel to the action potential duration without any influence on upstroke velocity or conduction parameters. The present double-blind, placebo-controlled study was designed to show the effect of dofetilide on basic electrophysiologic parameters in patients with coronary artery disease. Eighteen patients (aged 31 to 64 years) with symptoms of stable angina pectoris admitted for routine coronary angiography were recruited. They were randomly allocated to receive either placebo or 1 of 2 dose levels of dofetilide intravenously with 6 patients in each group. Paired electrophysiologic variables were compared before and after administration of dofetilide. Both active dose levels produced significant prolongations (p < 0.05) of 10 to 23% in atrial effective refractory period, 6 to 16% in ventricular effective refractory period and 11 to 15% in ventricular functional refractory period. Atrial functional refractory period was prolonged by 14 to 22% at the high-dose level (p < 0.05). No effect was observed on conduction parameters (PA, AH, HV, PR or QRS intervals), sinus cycle length or sinus node recovery. The selective prolongation of the refractory periods in both atrium and ventricle, combined with a lack of effect on cardiac conduction parameters, indicates that this drug could be useful in the treatment of both atrial and ventricular reentrant tachyarrhythmias and fibrillation.

Effects of Semotiadil (SD-3211), a Benzothiazine Calcium Antagonist, on Blood Pressure and Atrioventricular Conductivity in Anesthetized Dogs

We investigated the effects of semotiadil (SD-3211), a novel calcium antagonist, on blood pressure and the atrioventricular (AV) conduction time and functional refractory period (FRP) of the AV conduction system (AV conductivity) in anesthetized open-chest dogs. The heart was electrically stimulated at a constant rate. In dogs with an intact nerve supply to the heart, i.v.-injections of semotiadil (0.03 to 0.3 mg/kg) produced a fall of blood pressure in a dose-dependent manner. AV conduction time and FRP were prolonged by rather higher doses (0.3 mg/kg), and second-degree AV block occurred only with the highest dose (1 mg/kg). In dogs with the nerve supply to the heart interrupted, the vasodepressor effects and suppressant effects of semotiadil on AV conductivity were slightly enhanced. The suppressant effects on AV conductivity became marked as pacing rates were increased. These results suggest that semotiadil at appropriate doses produces a vasodepressor effect without affecting AV conductivity even in the heart deprived of nervous control, e.g., the heart with β-adrenoceptors blocked. The frequency-dependent suppressant effect on FRP of semotiadil is also noteworthy in the treatment of reentrant supraventricular tachycardia that involves the AV node.

Dofetilide, A Novel Class III Antiarrhythmic Agent

Summary: Dofetilide is a potent and selective class III antiarrhythmic agent that is under development for the treatment of re-entrant tachyarrhythmias (ventricular tachycardia/ventricular fibrillation, atrial fibrillation/atrial flutter, and paraoxysmal supraventricular tachy-cardia). In animal studies, dofetilide selectively inhibits the rapid component of the time-dependent outward potassium current (Ikr) and therefore increases the effective refractory period and action potential duration without affecting the fast inward sodium current. Studies in dogs have shown that dofetilide (a) prolongs the effective refractory period in a dose-dependent manner, (b) elevates ventricular fibrillation threshold, (c) facilitates conversion of electrically induced ventricular fibrillation or fibrilloflutter to sinus rhythm, (d) does not influence conduction within the His-Purkinje system or within the myocardium, (e) does not impair cardiac contractility, and (f) reduces dispersion of ventricular repolarization. Dofetilide has been administered to healthy volunteers as well as to patients with ischemic heart disease or with supraventricular arrhythmias; the compound has generally been well tolerated. Side effects have occasionally been reported, but have generally been transient and mild and occur in placebo-treated subjects as well. No clinically significant changes in laboratory safety tests have been detected. The pharmacokinetic profile of dofetilide both in healthy volunteers and patients includes a linear dose-plasma concentration relationship and also a linear plasma concentration-QT. relationship. The terminal plasma elimination half-life is approximately 9-10 h and systemic bioavailability in the region of 100%. The elimination pattern is balanced, with 50% being excreted unchanged via the kidney, the remaining 50% being metabolized in the liver to inactive metabolites, with greater than 90% of circulating drug-related material being unchanged do fetilide. After intravenous administration of the compound. a slight hysteresis in the plasma drug level-QT. relationship has been detected. Pharmacodynamic data demonstrate dose- and concentration-dependdent effects on myocardial repolarization as evidenced by prolongations of the QT. interval. This is reflected in significant prolongations in the effective and functional refractory periods and monophasic action potential duration throughout the myocardium. No effects on sinus node function, conduction parameters, or cardiac contractility have been detected in any of the clinical studies, supporting the contention that dofetilide is a highly selective class III antiarrhythmic agent.

Efficacy and electrophysiologic effects of oral sotalol in patients with sustained ventricular tachycardia caused by coronary artery disease

The efficacy of oral sotalol in preventing sustained ventricular tachycardia induction by invasive electrophysiological testing was assessed in 22 patients (60 ± 9 years) with prior myocardial intarction. Programmed stimulation consisted of two basic drives followed by up to three extrastimuli at two right ventricular sites. At baseline, sustained monomorphic ventricular tachycardia was inducible in all patients. With sotalol (360 ± 172 mg/day), it was no longer inducible in 10 patients; in 12 others, it remained inducible and its cycle length was only minimally prolonged (322 ± 42 to 345 ± 44 msec, p < 0.05). Sotalol markedly prolonged sinus cycle length, uncorrected QT interval, and right ventricular effective and functional refractory periods, but had little effect on ventricular conduction time either in sinus rhythm or with right ventricular pacing. There was no significant difference in drug dose or in electrophysiologic effect of drug that related to efficacy, nor was there any correlation between drug-induced prolongation of ventricular tachycardia cycle length and its effects. Six patients received oral sotalol over the long term without spontaneous recurrence of ventricular tachycardia (follow-up: 23 ± 18 months). These results demonstrate that sotalol is effective (45%) against sustained ventricular tachycardia induction at moderate doses and is well tolerated over a long term in the setting of remote myocardial infarction. However, its electrophysiologic effects as measured at invasive testing are not predictive of efficacy against ventricular tachycardia induction.

Reflex control of atrioventricular nodal refractory periods by cardiopulmonary receptors in humans.

The effects of selective cardiopulmonary receptor unloading on atrioventricular (AV) conduction were examined in 7 patients undergoing electrophysiologic testing. During -35 mmHg lower body negative pressure (LBNP) before autonomic blockade with propranolol and atropine, the AV-nodal conduction time (AH interval), the effective and functional refractory periods of AV node decreased at paced cycle length, when systemic arterial and central venous pressures decreased and heart rate increased. These responses to -35 mmHg LBNP except reductions in systemic arterial and central venous pressures disappeared after autonomic blockade. During -10 mmHg LBNP before autonomic blockade, both effective and functional refractory periods of AV node at paced cycle length decreased by 11 +/- 3% (mean +/- SEM) and 6 +/- 1% respectively with the reduction of central venous pressure while AH interval, systemic arterial pressure and heart rate remained unchanged. After autonomic blockade, -10 mmHg LBNP reduced central venous pressure but all the other parameters remained unchanged. These results suggest that cardiopulmonary baroreceptors participate in the reflex control of AV nodal refractoriness in humans.

The electrophysiological effects of flosequinan

We have evaluated the acute electrophysiological effects of flosequinan in 18 patients with normal ventricular function. Following intravenous infusion of flosequinan 100 mg over 1 h, mean (SD) systolic blood pressure fell from 131 +/- 19 to 120 +/- 22 mmHg (P less than 0.02) and there was significant shortening of sinus cycle length (732 +/- 151 to 575 +/- 93 ms, P less than 0.001), AH interval (110 +/- 45 to 71 +/- 19 ms, P less than 0.01), QRS duration (98 +/- 28 to 91 +/- 26 ms, P less than 0.02) and QT interval (373 +/- 47 to 337 +/- 35 ms, P less than 0.001), but no change in sinus node recovery time, intra-atrial conduction time, HV interval or the corrected QTc interval. There was a reduction in both anterograde atrioventricular Wenckebach cycle length (299 +/- 53 to 259 +/- 52 ms, P less than 0.01) and retrograde ventriculoatrial Wenckebach cycle length (375 +/- 77 to 300 +/- 56 ms, P less than 0.01). There was no change in atrial or ventricular effective refractory period (ERP) but atrial functional refractory period (FRP) shortened (233 +/- 31 to 212 +/- 24 ms, P = 0.07) as did ventricular FRP (249 +/- 24 to 234 +/- 21 ms, P less than 0.01). Patients received an oral dose of flosequinan 50 mg 12 h later. By 24 h, sinus cycle length, QRS duration and the QT interval had all returned towards baseline values, but ventricular ERP had lengthened (199 +/- 22 to 215 +/- 26 ms, P less than 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Inotropic and electrophysiological effects of BDF 9148, a congener of DPI 201–106, in guinea‐pig atria and papillary muscles

1. BDF 9148 is a newly synthesized congener of DPI 201-106 in which the piperazidinyl moiety has been replaced by an azetidine-3-oxy-moiety. The inotropic effect of both drugs was studied as well as their influence on the action potential, by use of standard microelectrode techniques. 2. BDF 9148 increased the contractile force of guinea-pig atria and papillary muscles. The EC50 was 1.32 X 10(-7) mol l-1 and 0.7 X 10(-6) mol l-1 respectively. DPI 201-106 was effective in a similar concentration-range, the EC50 being 2.6 X 10(-7) mol l-1 for atria and 2.8 X 10(-7) mol l-1 for papillary muscles. 3. Both drugs caused a concentration-dependent prolongation of the relaxation time of the isometric contraction curve. With 10(-6) mol l-1 BDF 9148, the mean increase was 39.1 +/- 4.4 ms in atria and 39.4 +/- 7.5 ms in papillary muscles while 10(-6) mol l-1 DPI 201-106 caused increases of 56.7 +/- 2.5 ms and 79.3 +/- 11.7 ms, respectively. The effect of BDF 9148 was not prevented by propranolol, but was reversed by 3 X 10(-6) mol l-1 tetrodotoxin. Pretreatment of atria with 3 X 10(-8) mol l-1 BDF shifted the concentration-response curve of ouabain to the left and reduced the EC50 of the glycoside from 3.21 X 10(-7) mol l-1 to 2 X 10(-7) mol l-1. 4. BDF 9148 and DPI 201-106 concentration-dependently increased the action potential duration of papillary muscles and their functional refractory period. The drugs did not modify the resting potential, the action potential amplitude or the maximum depolarization velocity.5. All effects of BDF 9148 persisted after washout. The lipophilic drug accumulated in the tissues and the tissue drug concentration was little reduced by washout of BDF 9148 from the organ bath.6. In contrast to DPI 201-106, which had a prominent negative chronotropic effect in right atria, BDF 9148 caused only a slight reduction of the beating frequency with the largest (3 x 10 5mol 11) concentration.7. The results are consistent with BDF 9148 being a sodium channel activator with much weaker influence on the beating frequency than the parent compound DPI 201-106.

Feasibility of closed heart discrete cryomodification of atrioventricular conduction: Electrophysiologic effects in the canine heart

Discrete cryosurgical modification of atrioventricular conduction abolishes refractory atrioventricular node reentry tachycardia with preservation of antegrade atrioventricular nodal conduction. This procedure presently requires cardiopulmonary bypass. To modify atrioventricular conduction without cardiac surgery, we evaluated the electrophysiologic effects of cryolesions applied to the peri-nodal area in the closed heart in 16 dogs before operation, during cryothermic exposure, and at 1 hour and 3 hours after operation. The electrophysiologic effects were evaluated in 10 of the 16 dogs at 2 weeks postoperatively. The dogs were given general anesthetics, and a cryoprobe was introduced into the right atrial cavity through the right atrial appendage. Cryolesions (-60 degrees C) were placed at nine to eleven preselected points around the perinodal area guided by electrodes on the tip of the cryoprobe. Postoperatively, there were significant prolongations of the atrio-His interval, Wenckebach's point, effective refractory period, and functional refractory period of the atrioventricular node. Atrial echo beats were eliminated or decreased in frequency. There was also a significant increase in retrograde ventriculoatrial conduction time. In the long-term observation period the atrio-His intervals remained significantly prolonged in comparison with the preoperative values, the atrial echoes progressively decreased, and ventriculoatrial conduction was absent in five of seven animals. A serendipitous atrioventricular node reentry tachycardia that was inducible in one animal with dual atrioventricular node conduction pathways was successfully eliminated and was not inducible at 2 weeks postoperatively. Complete atrioventricular block occurred during attempts to produce greater atrio-His prolongation in three of the 16 animals and persisted in two for the 2-week period of observation. Closed heart intracardiac cryomodification of atrioventricular conduction is feasible, with the cryoprobe in normothermic blood, producing changes in atrioventricular conduction similar to the open cardiac procedure.

Antiarrhythmic and proarrhythmic properties of diazepam demonstrated by electrophysiological study in humans

We evaluated the electrophysiological parameters before and after the intravenous infusion of diazepam (0.2 mg/kg) in 20 cardiac patients to investigate the drug's antiarrhythmic effect. Diazepam did not significantly change the arterial pressure. After the intravenous infusion of diazepam, the sinus cycle length significantly shortened from 847 +/- 132 to 747 +/- 155 ms (p less than 0.01). No significant change in the maximal sinus node recovery time was noted. The AH interval at the atrial pacing length of 600 ms shortened significantly from 140 +/- 40 to 127 +/- 39 ms (p less than 0.05). However, there was no significant change after the administration of diazepam in the longest atrial pacing rate associated with Wenckebach conduction in the atrioventricular (AV) node, effective and functional refractory periods of the AV node, HV interval, and QRS width during ventricular pacing at the cycle length of 600 ms. The atrial and ventricular effective refractory periods remained unchanged after the administration of diazepam. Six of the eight patients who showed dual AV nodal refractory period curves in the control study did not demonstrate them after diazepam administration by increasing the atrial or AV node effective refractory period. Thus, diazepam showed significant electrophysiological effects of the heart including shortening of the sinus cycle length, improvement in AV node conduction, and no significant effect on the His-Purkinje or intraventricular conduction and refractoriness of the atrium, AV node and ventricle. On the other hand, diazepam may influence the inducibility of supraventricular reentrant tachycardia incorporating the AV node.

Effects of Atrial Impulse Timing on AV Concealed Conduction in the Rabbit Heart

The influence of the timing of a nontransmitted or transmitted atrial impulse on the atrioventricular (AV) conduction time of the subsequent impulse was studied in nine isolated rabbit hearts. AV conduction curves were determined by applying the atrial extrastimulus test. The extrastimulus was delivered preceded or not by an interposed atrial impulse whose coupling interval with respect to the last atrial beat of a basic train was kept constant at 100, 120, 140, 160, 175, 200, 225, 250, and 300 msec. In all experiments, there was a "concealment interval," i.e., the AV effective refractory period was longer than the atrial functional refractory period, and in seven experiments was comprised between 100 and 160 msec. For any given extrastimulus coupling interval in the presence of an interposed nontransmitted atrial impulse, AV conduction time was significantly greater than in its absence; the increase was greater than the longer the nontransmitted atrial impulse coupling interval, i.e., the shorter the subsequent transmitted impulse coupling interval with respect to the previous interposed nontransmitted impulse. The AV conduction curves relating the extrastimulus AV conduction time to its coupling interval with respect to the last atrial impulse of the basic train fitted to a hyperbolic model both in the absence of the interposed atrial impulse and in its presence (mean square residual 31 +/- 23 msec2), and the interposed atrial impulse modified the constants of the functions; the slope of the linear transformations was progressively more negative as the interposed atrial impulse was delayed. Furthermore, the effects of the interposed atrial impulse--transmitted or not--on AV conduction time of the subsequent impulse were qualitatively similar, their magnitude depending on the time elapsed were qualitatively similar, their magnitude depending on the time elapsed between the two.

Identification of the rate-dependent functional refractory period of the atrioventricular node in simulated atrial fibrillation

We continuously observed successive pairs of R-R intervals during atrial fibrillation and hypothesized that the shortest R-R interval for a given preceding R-R interval in a pair represents the functional refractory period of the atrioventricular node at that preceding interval. To test this hypothesis we simulated atrial fibrillation in 28 isolated cross-perfused canine hearts and obtained an R-R interval scatterplot by plotting the R-R intervals as a function of the immediately preceding R-R interval. This scatterplot enabled us to detect a series of the shortest R-R intervals for a wide range of preceding R-R intervals, and this allowed us to estimate the rate-dependent functional refractory period of the atrioventricular node in simulated atrial fibrillation. The estimated functional refractory periods correlated well with those measured by the conventional method ( r = 0.93). We conclude that the proposed method makes it possible to estimate the rate-dependent functional refractory periods of the atrioventricular node in atrial fibrillation.

Drug response at electropharmacologic study in patients with ventricular tachyarrhythmias: The importance of ventricular refractoriness

The clinical and electrophysiologic predictors of successful antiarrhythmic drug therapy for patients with inducible ventricular tachycardia were evaluated in 59 consecutive patients undergoing serial electropharmacologic trials. Structural heart disease was less frequently present in patients for whom effective therapy was found (p < 0.05). The presence of coronary artery disease and a history of prior myocardial infarction were significantly more frequently present in patients for whom antiarrhythmic drug therapy could not be found (p < 0.05). The corrected QT interval and ventricular effective refractory period measured at a pacing cycle length of 400 ms were significantly shorter in responders compared with nonresponders (QT interval 428 ± 52 versus 460 ± 59 ms; ventricular effective refractory period 237 ± 28 versus 254 ± 24 ms; (p < 0.05). In addition, the interelectrogram coupling interval of the ventricular extrastimulus initiating ventricular tachycardia was significantly shorter in responders compared with nonresponders (223 ± 37 versus 251 ± 33 ms; p = 0.003).Logistic regression analysis identified a short ventricular inter-electrogram coupling interval (p < 0.01) end absence of prior myocardial infarction (p < 0.05) as the only independent predictors of antiarrhythmic drug suppression of the induction of ventricular tachycardia. Greater drug-induced increments in the ventricular effective and functional refractory periods were observed in responders than in nonresponders as was the shortest ventricular interelectrogram coupling interval.Thus, baseline electrophysiologic measurements identify patients with inducible ventricular tachycardia who are likely to respond to antiarrhythmic drag therapy. Furthermore, these patients demonstrate greater drug-induced electrophysiologic changes.