Frequency-dependent effects of quinidine on the ventricular action potential and QRS duration in humans

We studied the frequency-dependent effects of quinidine on the right ventricular action potential and QRS duration in 10 patients (nine men and one woman; mean age, 57 +/- 14 years) undergoing electrophysiologic studies for clinical indications. The right ventricular monophasic action potential, electrocardiographic, and conventional intracardiac electrical signals from various sites were recorded at different pacing cycle lengths from 30 seconds to 1 minute before and after a 10-mg/kg i.v. quinidine infusion. We used the extrastimulus technique to determine the effects of quinidine on ventricular refractory periods at different pacing cycle lengths and on the abrupt changes of the action potential duration. The action potential duration progressively decreased as the ventricular pacing rate increased at baseline and after quinidine infusion. Quinidine significantly increased the action potential duration from that of control by 25 msec (p less than 0.02) at the relatively slow pacing cycle lengths of 600, 500, and 400 msec. Quinidine's effect on the action potential duration was attenuated at the pacing cycle length of 350 msec and became negligible at 300 msec. In contrast, quinidine progressively lengthened the QRS duration as the pacing rate increased (20, 18, 37, 46, and 34 msec at pacing cycle lengths of 600, 500, 400, 350, and 300 msec, respectively; p less than 0.05). There were no rate-dependent changes in the QRS duration during the control period. The relation between the ventricular refractory periods and the action potential duration at different pacing cycle lengths was also determined before and after quinidine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of the class III antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and QT interval dispersion in stable angina pectoris.

The effects of intravenous dofetilide on ventricular monophasic action potential duration and effective refractory period at the right ventricular apex and outflow tract were studied in 18 patients (aged 37 to 70 years) with ischemic heart disease. Six patients received low-dose dofetilide as a 3 micrograms/kg loading dose over 15 minutes and a 1.5 micrograms/kg maintenance dose over 45 minutes; 6 received high-dose dofetilide 6 + 3 micrograms/kg and 6 placebo. During atrial pacing at a cycle length of 800 ms high-dose dofetilide prolonged right ventricular apex monophasic action potential duration by 45 ms (16%) and the effective refractory period by 40 ms (16%). At the right ventricular outflow tract, monophasic action potential duration was prolonged by 45 ms (15%) and effective refractory period by 55 ms (21%). During atrial pacing at a cycle length of 500 ms high-dose dofetilide prolonged the right ventricular apex monophasic action potential duration by 40 ms (18%) and the effective refractory period by 43 ms (21%). The right ventricular outflow tract monophasic action potential duration was prolonged by 33 ms (14%) and effective refractory period by 45 ms (21%). Dofetilide produced no increase in the dispersion of repolarization between the 2 sites. During the maintenance infusion QTc prolongation by high-dose dofetilide averaged 43 ms (10%) with no increase of interlead QT dispersion. The effects of dofetilide on QT interval and effective refractory period are shown to be due to a direct effect on action potential duration with no effect on dispersion. No rate dependence of monophasic action potential prolongation was detected at these cycle lengths.     

Subthreshold conditioning stimuli prolong human ventricular refractoriness

This study tested whether a subthreshold stimulus (Sc) inserted before a premature stimulus prolonged the right ventricular effective refractory period in humans, and whether the degree of effective refractory period lengthening was influenced by heart rate, Sc current intensity or Sc pulse duration. Sc at current intensity 10 mA and pulse width 2 ms prolonged mean effective refractory period from 255 ms to 277 ms (p less than 0.001, n = 20). The increase in effective refractory period was similar in 6 patients studied at pacing cycle lengths 600 (259 to 289 ms) and 400 ms (236 to 258 ms). When Sc current intensities were varied at 2, 5 or 10 mA at a constant pulse duration of 100 ms the effective refractory period progressively prolonged by 6, 40 and 81 ms respectively (p less than 0.02, n = 6). The pulse duration of Sc at a constant current of 10 mA significantly influenced effective refractory period prolongation. With Sc pulse durations of 2, 10, and 100 ms the effective refractory period prolonged by 16, 33 and 66 ms respectively (p less than 0.01, n = 7). Thus, subthreshold impulses prolong the effective refractory period in human right ventricular myocardium. The prolongation of effective refractory period depended on Sc current intensity and pulse duration but was independent of heart rate at the cycle lengths tested. The use of subthreshold stimuli as antiarrhythmic therapy may be feasible in some patients.     

Monophasic action potentials in patients with coronary artery disease: reproducibility and electrical restitution and conduction at different stimulation rates

Monophasic action potentials were recorded in the outflow tract of the right ventricle in patients with coronary artery disease during ventricular pacing at different basic cycle lengths and programmed stimulation. During continuous pacing (basic cycle length 600 ms) the time for 90% repolarisation (MAP90) and the QTa interval decreased exponentially during the first 1.5-2 min of pacing to 90% of control values. The reproducibility of the monophasic action potential signals and the ventricular effective refractory period were assessed as good when studied after repetitive trains of 8 beats for more than 1.5 min. The reproducibility of conduction, however, was less good. Electrical restitution of MAP90 duration of the premature beats determined at three different basic cycle lengths was different from that in single muscle preparations. The curves showed two phases with unchanged MAP90 durations despite longer coupling intervals. The first phase was close to the ventricular effective refractory period, probably because subnormal conduction left the diastolic interval constant for the earliest premature beats. This indicates that subnormal conduction may influence the premature dispersion of repolarisation.     

Effect of mexiletine on monophasic action potentials recorded from the right ventricle in man.

The effect of mexiletine, a new antiarrhythmic agent, on ventricular refractoriness and monophasic action potentials recorded from the right ventricle was studied in nine subjects. The effective refractory period of the right ventricle was determined by the extra stimulus technique using a pacing electrode situated at the right ventricular apex. Following this determination the right ventricular apex was paced at a constant cycle length and premature stimuli were introduced starting at a coupling interval of 2 ms greater than the ventricular refractory period and then at progressively increasing coupling intervals of 5 ms increments. Simultaneous recordings of monophasic action potentials of both the regular paced beats and the induced premature beats were made using a specially designed suction electrode catheter. The monophasic action potential durations were measured at 50% and 90% repolarisation. All these control measurements were repeated after an intravenous dose of 2 mg.kg-1 body wt. of mexiletine. The results showed that mexiletine did not significantly change the effective ventricular refractory period nor did it alter the monophasic action potential duration of the regular paced beat. The drug did, however, significantly prolong the monophasic action potential duration of the early induced premature beats and it is possible that this property of the drug may be related to its antiarrhythmic activity.     

The human atrial strength-interval relation. Influence of cycle length and procainamide

We defined the atrial strength-interval relation in 23 patients at cycle lengths of 600, 450, and 300 msec before and after procainamide. The atrial diastolic threshold was similar at cycle lengths of 600 and 450 msec, but the threshold at 300 msec was significantly higher than that determined at 600 and 450 msec both before and after procainamide. Procainamide significantly increased the diastolic threshold only at a cycle length of 300 msec. The strength-interval relation was nonlinear, showing progressively decreasing decrements in the measured refractory period as the stimulating current was increased. Progressive decreases in the drive cycle length from 600 to 450 to 300 msec caused similar decreases in refractory periods. The shape of the curves was similar at cycle lengths of 600 and 450 msex. However, at low current strengths, the slope of the curve determined at 300 msex was significantly more vertical than the slopes of the curves at the longer drive cycle lengths. Procainamide caused similar increases in apparent refractory periods at each paced cycle length. Procainamide did not alter the shape of the curves at any paced cycle length. These observations confirm the importance of stimulation frequency on atrial excitability. They suggest that the effects of procainamide on the effective refractory period of the atrium are not cycle length dependent, although the drug effects on threshold are dependent on the drive cycle length.     

Beneficial effect of amiodarone on pacing induced terminability of reentrant ventricular tachycardia

A 33 year-old woman was referred to our hospital for further treatment of ventricular tachycardia (VT). During treatment with amiodarone (200 mg/day), clinical VT at the cycle length of 510 ms was induced. During the VT, rapid ventricular pacing was repeated at progressively shorter cycle lengths after a decrement of 10 ms steps. The VT was entrained by the rapid pacing and reproducibly terminated at a paced cycle length of 380 ms. Four weeks after reducing the amiodarone to 100 mg/day, programmed stimulation was repeated. The VT with the same morphology but with a slightly shorter cycle length of 480 ms was again induced. However, at this time, rapid pacing from the same site could not terminate VT and transient acceleration developed at a shorter paced cycle length of 260 ms. The QT (QTc) interval, effective refractory period at the pacing site and width of the paced QRS complex were similar before and after changing the amiodarone treatment. The most characteristic change of VT in the second study was a widening of the entrainment zone, which was calculated as the difference between VT cycle length and the longest pacing cycle length which interrupts VT during the entrainment (from 130 to > 220 ms), and it may be explained by the preferential shortening of the action potential duration and/or facilitation of the depressed cell to cell conduction within the reentry circuit. Amiodarone must exert a preferential action in the reentry circuit and modulate the conduction property as well as the effective refractory period. We should pay close attention to the efficacy of antitachycardia pacing during the modification of amiodarone treatment.     

Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs.

Flecainide is effective against certain supraventricular arrhythmias (atrial fibrillation and atrioventricular [AV] node reentrant tachycardia), but its mechanisms of action are unknown. Previous in vitro work suggests that flecainide attenuates rate-dependent action potential duration shortening, producing tachycardia-dependent prolongation of the refractory period. This study was designed to assess whether similar changes occur in vivo and whether the effects of flecainide on AV node conduction depend on heart rate and on direction of propagation (anterograde vs. retrograde). The effects of flecainide at three clinically relevant concentrations were assessed in open chest, morphine-chloralose-anesthetized dogs. Flecainide increased atrial refractory period in a concentration- and rate-related fashion (e.g., dose 3 increased the atrial effective refractory period by 9 +/- 4% at a cycle length of 1,000 ms but by 36 +/- 5% and 55 +/- 10% at a basic cycle length of 400 and 300 ms, respectively; p less than 0.001 for each). Flecainide attenuated the action potential duration accommodation (measured by monophasic action potentials) to heart rate, causing tachycardia-dependent action potential duration prolongation and accounting for most of the rate-dependent atrial effective refractory period changes. Flecainide increased Wenckebach cycle length, but the concentration-response curve was much steeper in the retrograde (slope 41 +/- 7 ms/mumol.liter-1) than in the anterograde direction (17 +/- 4 ms/mumol.liter-1; p less than 0.01), indicating more potent effects on retrograde conduction. The depressant action of the drug on the AV node was also rate dependent, with an effect on the AH interval at a basic cycle length of 400 ms that averaged 1.8, 1.5 and 2 times that at a basic cycle length of 1,000 ms for doses 1 (p less than 0.05), 2 (p less than 0.01) and 3 (p less than 0.001), respectively. Conclusions: 1) Flecainide suppresses atrial action potential duration accommodation to heart rate changes in vivo, leading to rate-dependent atrial effective refractory period prolongation, which may be important in suppressing atrial fibrillation. 2) The drug has frequency- and direction-dependent effects on AV node conduction, which may lead to selective antiarrhythmic actions during AV node reentry.     

Influence of i.v. haloperidol on ventricular repolarization and monophasic action potential duration in anesthetized dogs

INTRODUCTION: i.v. haloperidol is used commonly for sedation in critically ill patients. However, i.v. haloperidol has been shown to cause the life-threatening ventricular tachyarrhythmia torsades de pointes. Mechanisms by which haloperidol causes torsades de pointes have not been widely investigated in controlled studies. STUDY OBJECTIVES: To determine the effects of i.v. haloperidol on electrophysiologic parameters known to promote torsades de pointes. INTERVENTIONS: Monophasic action potential catheters were guided under fluoroscopy into the right and left ventricles of 14 chloralose-anesthetized dogs (haloperidol, nine dogs; placebo, five dogs). Effective refractory period (ERP), action potential duration at 90% repolarization (APD90), and QTc interval measurements were performed at baseline and after each of four doses of haloperidol (0.15, 0.5, 2.0, and 3.0 mg/kg) or placebo at three different pacing cycle lengths (450, 300, and 250 ms). MEASUREMENTS AND RESULTS: i.v. haloperidol significantly prolonged left and right ventricular ERP by a magnitude of 12 to 20% at all pacing cycle lengths. ERP values in the placebo group did not change significantly from pretreatment values in either ventricle. Haloperidol significantly prolonged left ventricular APD90 at a pacing cycle length of 300 ms. The effects of haloperidol on right ventricular APD90 approached significance at a cycle length of 450 ms. Overall, haloperidol prolonged APD90 by 7 to 11%, with less consistent and more variable effects than those for the ERP. APD90 was not significantly altered in the placebo groups. Haloperidol produced significant prolongation in QTc intervals. The electrophysiologic effects of haloperidol were related to dose, with a plateau reached at the 0.5 mg/kg dose for ERP measurements and at the 2 mg/kg dose for the APD90 and QTc interval measurements. CONCLUSIONS: i.v. haloperidol prolongs ventricular ERP and APD90 in intact canine hearts. These electrophysiologic effects are likely associated with the clinical torsades de pointes-inducing actions of i.v. haloperidol in critically ill patients.     

Alterations in atrial electrophysiology associated with chronic atrial fibrillation in man.

BACKGROUND: The purpose of this study was to determine the changes in atrial electrophysiology associated with chronic persistent atrial fibrillation in man. METHODS AND RESULTS: Atrial monophasic action potential duration at 90% repolarization and the effective refractory period were measured in 13 patients with chronic persistent atrial fibrillation after low-energy endocardial cardioversion, and compared to eight controls without a history of atrial fibrillation. Measurements were made at the right atrial appendage and midlateral right atrial wall at basic, 600 ms and 400 ms drive cycle lengths. In control patients, the effective refractory periods were significantly longer at the atrial appendage than the lateral wall at 600 ms (right atrial appendage 265 ms, midlateral right atrial wall 228 ms, P<0.05), and 400 ms cycle lengths (right atrial appendage 270 ms, midlateral right atrial wall 218 ms, P<0.05), but this was not evident in patients with atrial fibrillation. The monophasic action potentials and effective refractory periods at both atrial sites were shorter in the atrial fibrillation patients compared to controls; however, only the effective refractory periods at atrial appendage at 600 ms (atrial fibrillation 210 ms, controls 265 ms, P<0.001), and 400 ms cycle lengths (atrial fibrillation 200 ms, controls 270 ms, P>0.001) reached statistical significance. Effective refractory period dispersion was significantly greater in controls than in patients with atrial fibrillation (cycle length 600 ms: controls 36, atrial fibrillation 13, P=0.01; cycle length 400 ms: controls 54, atrial fibrillation 18, P<0.01). CONCLUSIONS: In patients without a history of atrial fibrillation, the refractory period at the right atrial appendage is significantly longer than at the midlateral right atrial wall. This 'normal' pattern of atrial refractory dispersion is lost in patients with chronic persistent atrial fibrillation, with marked shortening of the effective refractory period at the right atrial appendage. This may explain the high risk of recurrence of atrial fibrillation following successful electrical cardioversion.     

Modulation of collision-induced changes in canine heart repolarization by cycle length

The possibility that cycle length modulates the electronic effect of activation sequence on repolarization was investigated in experiments using isolated canine cardiac Purkinje strands, in situ canine ventricular myocardium, and computer simulations. Action potential durations and refractory periods during one-way propagation were compared to those obtained during action potential collision. In both the computer simulations and the Purkinje strand experiments, collision decreased action potential duration more at long cycle lengths than at short cycle lengths. Comparably, collision of activation fronts in ventricular myocardium was associated with greater reductions in refractory period during pacing at long cycle lengths than at short cycle lengths. Theoretic considerations indicate that the magnitude of electrotonic effects of activation sequence on repolarization are directly related to action potential height and the square root of membrane resistance during repolarization and are inversely related to conduction velocity. In computer simulations and Purkinje strand experiments, changes in conduction velocity and action potential height elicited by decreasing cycle length could not fully account for the cycle length dependence of collision-induced changes in repolarization. Time-varying membrane resistance of a single cell was calculated in the simulations by briefly hyperpolarizing the membrane and determining the change in total ionic current. Membrane resistance during repolarization was less at short cycle lengths than at long cycle lengths. The results suggest the cycle length dependence of collision-induced changes in repolarization results largely from the effect of cycle length on membrane resistance during action potential repolarization, with changes in action potential height and conduction velocity playing a lesser role.     

Effect of sotalol on human atrial action potential duration and refractoriness: cycle length dependency of class III activity

Using intracardiac electrophysiological techniques the effects of sotalol hydrochloride were studied in the right atrium in eight patients with paroxysmal supraventricular atrial arrhythmias. Atrial action potential duration was recorded from two well separated standard sites via endocardial contact electrodes before and for 30 minutes after intravenous sotalol (1 mg X kg-1). Atrial effective refractory period and vulnerability to atrial arrhythmia initiation were assessed by premature extrastimulation. All patients developed a prolonged action potential duration (mean +6%, p less than 0.01 in high atrial site; +8%, p less than 0.01 in low atrial site), with similar increases in atrial effective refractory period (mean +9%, p less than 0.01). The small regional difference in action potential duration detected between these well separated recording sites was minimally decreased, indicating no tendency towards increased regional inhomogeneity of repolarisation. The relatively refractory zone as denoted by the gap between atrial effective refractory period and action potential duration was slightly reduced, and transient repetitive atrial depolarisations, initially provoked by extrastimuli in two patients, were abolished. The relation between atrial interval and duration, investigated using two modes of paced cycle length modification, showed that a gradual reduction in pacing cycle length was more potent in shortening action potential duration than was isolated premature extrastimulation. Sotalol was significantly more effective in opposing shortening of the action potential duration caused by progressive cycle length reduction than that caused by isolated extrastimulation. The class III antiarrhythmic activity of sotalol, confirmed in the atrium, is dependent on cycle length and mode of cycle length alteration. Under study conditions, there was no tendency to increase atrial vulnerability or regional non-uniformity of repolarisation.     

Time dependence of ventricular refractory periods: implications for electrophysiologic protocols

Cardiac refractory periods are routinely measured during electrophysiologic testing. Informal observations suggested that the effective refractory period lengthened with a prolongation of the time in sinus rhythm (basic cycle length time) between successive runs of drive stimuli (S1S1s). If this were true, failure to control the basic cycle length time could affect the results and interpretation of electrophysiologic testing. To study this phenomenon, the effective refractory period was studied in 20 patients during sinus rhythm and two ventricular paced rates with up to three extrastimuli, while varying the basic cycle length time from 2 to 3, to 10 to 20 s. With each of the stimulation sequences used, the effective refractory period lengthened as the basic cycle length time increased ("basic cycle length time-effective refractory period effect"). The effect was most pronounced when extrastimuli were used during the two ventricular paced rates. As the basic cycle length time increased from 2 to 3 to 20 s, the mean effective refractory period determined during sinus rhythm increased from 296 to 300 ms; with the first ventricular paced rate, the effective refractory period increased from 259 to 272 ms (p less than 0.0003) and with the second ventricular paced rate, the effective refractory period increased from 250 to 263 ms (p less than 0.01). The basic cycle length time-effective refractory period effect became more pronounced as the number of extrastimuli increased. With the second ventricular paced rate, as basic cycle length was increased from 2 to 3 to 20 s, the mean prolongation in the cumulative effective refractory period (S1 to final extrastimulus) as the number of extrastimuli increased from 1 to 2 to 3, was 13 (p less than 0.01), 42 (p less than 0.0003) and 82 ms (p less than 0.001), respectively. Results were confirmed in 17 instances by redetermining the effective refractory period at the 2 to 3 s basic cycle length time after the final 20 s basic cycle length time determination, and demonstrating that it was similar to the effective refractory period after the initial 2 to 3 s basic cycle length time. No further prolongation of the effective refractory period could be demonstrated by increasing basic cycle length time from 20 to 60 s, and no significant effect of medications on the basic cycle length time-effective refractory period effect could be demonstrated.     

Human ventricular refractoriness: Effects of increasing current

The ventricular effective refractory period is commonly employed as a measurement of ventricular excitability. Because the current strength used to make this determination varies among laboratories, the relation of refractoriness and current was examined over a range of current strengths from 0.1 to 10 mA. Sixty determinations of refractoriness at variable current strengths were made in 40 patients using the extrastimulus technique with a rectangular pulse of 1 ms duration. These data were obtained by measuring the effective refractory period at threshold current and at 0.25 to 0.50 mA increments from threshold up to 10 mA. In these studies the drive stimulus (S₁) and extrastimulus (S₂) were kept at the same amplitude. In all patients the ventricular effective refractory period decreased as the current increased. The total decrease ranged from 8 to 100 ms (mean ± standard deyiation 36.9 ± 17.1). The current strength at which the ventricular effective refractory period became fixed (that is, less than 2 ms change in ventricular effective refractory period with further increase in current strength) varied among the patients, but in all instances equaled or exceeded 1.8 mA, which in all but three patients was greater than three times threshold. The curves relating current strength and refractoriness were shifted to the left at shorter cycle lengths with no change in threshold.These data suggest that (1) current strength-effective refractory period curves more completely characterize ventricular excitability than does a ventricular effective refractory period at single current strength; and (2) studies of drug effects, alterations of autonomic tone, or reentrant arrhythmias, which may affect or are affected by ventricular refractoriness, may be enhanced by more complete measurements of refractoriness afforded by the current strength-effective refractoriness curves.     

Comparison of individual and combined effects of procainamide and amiodarone in patients with sustained ventricular tachyarrhythmias

To compare the individual and combined electrophysiological effects of amiodarone and procainamide, 35 patients with sustained ventricular arrhythmias underwent programmed stimulation in the control state, after procainamide (mean concentration, 8.7 +/- 2.8 micrograms/ml), after 13 +/- 2 days of amiodarone (1,400 mg/day x 7 days, then 400 mg/day), and after amiodarone with procainamide (mean procainamide concentration, 7.8 +/- 2.2 micrograms/ml). Sustained ventricular tachycardia (VT) was inducible in all 35 patients during treatment with procainamide alone and with amiodarone alone. Procainamide and amiodarone similarly increased the VT cycle length (+68 vs. +61 msec), the corrected QT interval (+63 vs. +49 msec), and the ventricular effective refractory period measured at paced cycle lengths of 600-550 msec (+23 vs. +21 msec) and 400 msec (+25 vs. +23 msec). Procainamide had a more pronounced effect on QRS duration than amiodarone during sinus rhythm (+18 vs. +8 msec, p less than 0.01) and during paced cycle lengths of 600-550 msec (+32 vs. +23 msec, p less than 0.01) and 400 msec (+37 vs. +28 msec, p less than 0.1) but a similar effect on the QRS duration during VT (+32 vs. +29 msec). During combination therapy, VT initiation was prevented in only two (6%) patients. The combination therapy produced a greater increase (p less than 0.001) than individual therapy in all the electrophysiological intervals assessed, with the exception of the sinus cycle length. On each drug regimen, a cycle length-dependent increase (p less than 0.05) in paced QRS duration was noted (400 more than 600-550 msec).(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic substrate associated with pacing-induced heart failure in dogs: potential value of programmed stimulation in predicting sudden death.

To investigate the possible mechanisms of sudden death and the potential role of electrophysiologic testing in congestive heart failure, this study evaluated the electrophysiologic substrate in a model of heart failure induced by rapid pacing. Seventeen mongrel dogs underwent cardiac pacing at 220 to 240 beats/min for 5 weeks (paced group) and 11 other dogs served as a sham-operated control group. Rapid pacing of the right ventricle produced clinical and hemodynamic features of congestive heart failure. Dogs in the paced group had prolonged cardiac conduction time as reflected by longer epicardial activation time (36.1 +/- 2.4 vs. 30.8 +/- 0.8 ms, p less than 0.05). The ventricular effective refractory period was significantly prolonged after the development of heart failure (141 +/- 4 vs. 177 +/- 5 ms, p less than 0.01, at a basic pacing cycle length of 300 ms), whereas no significant change was found in the control group (140 +/- 4 vs. 145 +/- 4 ms, p = NS). The prolongation of the ventricular effective refractory period correlated with an increase in left ventricular end-diastolic pressure (r = 0.55, p less than 0.001) and the ventricular effective refractory period correlated inversely with cardiac index (r = -0.49, p less than 0.025). The rest membrane potential of ventricular muscle was less negative in the paced group compared with the control group (-80.7 +/- 2.2 vs. -85.6 +/- 2.2 mV, p less than 0.05). Intracellularly recorded action potential duration of ventricular muscle was longer in the paced than in the control group (236 +/- 9.8 vs. 198.9 +/- 2.6 ms, p less than 0.01), action potential duration at 90% repolarization).(ABSTRACT TRUNCATED AT 250 WORDS)     

Programmed ventricular stimulation in patients with left ventricular dysfunction and ventricular tachycardia: effects of acute hemodynamic improvement due to nitroprusside

To assess the electrophysiologic effects of acute hemodynamic improvement in patients with left ventricular systolic dysfunction, 12 patients with a left ventricular ejection fraction less than 0.40 and a history of sustained monomorphic ventricular tachycardia were studied. All patients had underlying coronary artery disease. Patients underwent programmed cardiac stimulation in random order during a baseline period and with nitroprusside infusion. Mean pulmonary capillary wedge pressure decreased from 20 +/- 8 mm Hg at baseline study to 8 +/- 3 mm Hg during nitroprusside infusion (p less than 0.0001). Pulmonary artery, right atrial and systemic arterial pressures also decreased with nitroprusside (p less than 0.01). Cardiac output did not change. Left ventricular dimensions, determined by two-dimensional echocardiography, decreased significantly during nitroprusside infusion. The right ventricular effective refractory period, measured during ventricular drive trains at cycle lengths of 400 and 600 ms, were similar during baseline and nitroprusside periods (271 +/- 30 versus 274 +/- 31 ms at 600 ms, and 249 +/- 25 versus 246 +/- 18 ms at 400 ms). In 2 patients no ventricular arrhythmias were induced during either study period; in the other 10, ventricular tachyarrhythmias were induced during both periods. The mean number of extrastimuli required to induce a ventricular tachyarrhythmia was similar during the baseline period (1.8 +/- 0.6) and during nitroprusside infusion (1.9 +/- 0.7). As well, the mean cycle length of ventricular tachycardia induced was similar during the baseline period (347 +/- 61 ms) and during nitroprusside infusion (342 +/- 70 ms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence that cocaine slows cardiac conduction by an action on both AV nodal and His-Purkinje tissue in the dog

The effects of intravenous cocaine (2 mg/kg) were tested on several indices of cardiac electrical activity in sedated dogs. These included sinus rate, PR, AH, and HV intervals; AV nodal effective refractory period (AVNERP); ventricular effective refractory period; QRS duration; and the QT interval. Cocaine induced significant changes in six control animals with an intact-functioning autonomic nervous systems. After pharmacologic autonomic blockade with propranolol plus propantheline, cocaine increased the PR interval (+ 11 +/- 4.0 ms, p less than 0.05), primarily by slowing conduction at the AV nodal level. However, with constant atrial pacing at a rate above the sinus cycle length, prolongation of both the AH and the HV intervals (+ 15 +/- 2.5 and 6.7 +/- 1.7 ms, respectively) occurred. There was also a significant increase in the AVNERP (+ 29 +/- 5.9 ms, p less than 0.05). Consistent with the observed rate-dependent HV prolongation, cocaine decreased the rate of rise of phase 0 of the transmembrane action potential of Purkinje fibers. These data indicate that cocaine impairs cardiac conduction by direct actions on AV nodal and His-Purkinje cells.     

Prolongation of the human cardiac monophasic action potential by sotalol

Sotalol and propranolol are nonselective beta-adrenergic blocking agents. Sotalol at low concentration, unlike propranolol, prolongs the duration of the transmembrane action potential. In a double-blind study, the electrophysiologic effects of intravenous sotalol (0.30 or 0.60 mg/kg; n = 9) were compared with intravenous propranolol (0.15 or 0.20 mg/kg; n = 8) in 17 patients with use of bipolar suction electrodes in the right atrium and right ventricle to determine whether sotalol prolongs the monophasic action potential duration in man. After administration of sotalol, there were significant increases (paired t test) in the Q-T interval (p less than 0.001), right atrial effective refractory period (p less than 0.05), right ventricular effective refractory period (p less than 0.005), right atrial monophasic action potential duration at 90% repolarization (p less than 0.01), and right ventricular monophasic action potential duration at 90% repolarization (p less than 0.005). Prolongation of the monophasic action potential duration was dependent on plasma sotalol concentration. There were no significant changes in these variables after propranolol. The spontaneous cycle length and Wenckebach cycle length increased significantly in both groups, and the mean blood pressure decreased in both, although not significantly after propranolol. In summary, sotalol but not propranolol prolonged atrial and ventricular effective refractory periods and lengthened the monophasic action potential and the Q-T interval of human myocardium after intravenous infusion. The ability to acutely prolong repolarization at therapeutic plasma concentration is unique among known competitive beta-adrenergic receptor antagonists.     

Postrepolarization Refractoriness as a Potential Anti–Atrial Fibrillation Mechanism of Pilsicainide, a Pure Sodium Channel Blocker with Slow Recovery Kinetics

The antifibrillatory effect of pilsicainide, a sodium channel blocker with slow recovery kinetics, was investigated in a canine model of atrial fibrillation. Prolonging the atrial effective refractory period is an important mechanism for pharmacological termination of atrial fibrillation. However, the effectiveness of potassium channel blockers has been questioned because of their reverse-use–dependent property. In eight open-chest dogs, the duration of the atrial endocardial monophasic action potential and the atrial effective refractory period were determined using a Franz catheter. Conduction velocity was obtained from a 96-channel mapping electrode at multiple cycle lengths. Inducibility of sustained atrial fibrillation (>30 minutes) was confirmed by atrial burst pacing during bilateral vagal stimulation, and local fibrillation cycle lengths were measured. Five minutes after restarting fibrillation, pilsicainide (0.6 mg/kg + 0.04 mg/kg/min) was administered. After fibrillation was terminated, measurements were repeated. Pilsicainide successfully terminated atrial fibrillation in 7 of 8 dogs after the median time of 5.1 minutes. The conduction velocity decreased significantly. Although pilsicainide did not affect monophasic action potential duration, it caused use-dependent prolongation of the atrial effective refractory period (P < 0.05), creating postrepolarization refractoriness. Accordingly, pilsicainide prolonged the atrial fibrillation cycle length from 80.6 to 113.8 ms (P < 0.05) before termination of fibrillation. Sodium channel blockers with slow recovery kinetics can prolong the atrial effective refractory period without affecting monophasic action potential duration. Unlike potassium channel blockers, these sodium channel blockers maintain postrepolarization refract