Clinical electrophysiologic effects of encainide, a newly developed antiarrhythmic agent.

Encainide is a newly developed antiarrhythmic agent. With the use of intracardiac electrophysiologic techniques, its effects on the cardiac conduction system were examined in 10 patients with coronary artery disease. Five patients received 0.6 and five received 0.9 mg/kg body weight of encainide intravenously over 15 minutes. Plasma concentration, heart rate, blood pressure and conduction intervals (A-H, H-V, QRS and Q-T) were measured before, during and after encainide infusion. In addition, sinus nodal recovery time, Wenckebach cycle length, and atrial, atrioventricular (A-V) nodal and right ventricular refractory periods were measured before and after encainide infusion. The average peak plasma concentration was 0.49 +/- 0.35 microgram/ml (mean +/- standard error of the mean). Encainide significantly prologned H-V and QRS intervals in all patients by an average of 31 +/- 7 and 18 +/- 9 percent (standard deviation) (P less than 0.001), respectively. A minimal increase in the Q-T interval was also observed after encainide infusion (2 +/- 9 percent, P less than 0.01), but no significant changes were noted in heart rate, blood pressure, A-H interval, corrected sinus noal recovery time, Wenckebach cycle length or refractory periods of the atrium, A-V node or right ventricle. It is concluded that encainide significantly prolongs conduction in the His-Purkinje system without affecting conduction or refractoriness of other parts of the cardiac conduction system in man.     

One to one atrioventricular conduction during atrial pacing at rates of 300/minute in absence of wolff-parkinson-white syndrome

One to one atrioventricular (A-V) or atrio-His bundle (A-H) conduction occurred during right atrial pacing at rates of 300/min in two patients with short P-R (and A-H) intervals, narrow QRS complexes and recurrent supraventricular tachyarrhythmias. Patient 1 had episodes of reciprocating A-V tachycardia and of atrial fibrillation with very fast rates (270 to 290/min) that were slowed to 100 to 135/min after administration of intravenous verapamil. Enhanced A-V (A-H) conduction was exposed only during stimulation from the high right atrium, but not from the low lateral right atrium or coronary sinus. Patient 2 had episodes of atrial flutter with 1:1 A-V conduction and rates of 290/min. The H-V interval was short (25 ms) during sinus rhythm and atrial pacing presumably because conduction occurred through an atrio-“distal” His bundle (atriofascicular) tract. In contrast, the H-V interval was normal (40 ms) in echo beats or when the “proximal” His bundle was stimulated.In these two patients, having as “common denominators” short P-R (and A-H) intervals, narrow QRS complexes and recurrent supraventricular tachyarrhythmias, enhanced A-V (A-H) conduction was (1) possibly due to different electrogenetic mechanisms; (2) pacing-site dependent; (3) manifested, during atrial fibrillation and atrial flutter, by extremely fast ventricular rates; and (4) unrelated to the rate of reciprocating A-V tachycardias because the latter was predominantly a function of anterograde conduction through the “slow” nodal pathway.     

Electrophysiologic effects of N-acetylprocainamide in human beings

The electrophysiologic properties of N-acetylprocainamide (NAPA) were studied in 10 patients undergoing cardiac catheterization. Each patient received two successive intravenous infusions: one loading infusion over 15 minutes and one maintenance infusion at a slower rate for 30 minutes. Eight patients received 10.5 mg/kg body weight and two received larger doses (16 and 21 mg/kg, respectively). NAPA plasma concentration was measured at 5 minute intervals from 0 to 25 minutes, and then at 15 and 30 minutes of the second infusion. Mean blood pressure and electrophysiologic data obtained by programmed stimulation were recorded before drug administration and at 15 and 30 minutes of the infusion when the concentration of NAPA was nearly constant in each patient (range 12 to 35 microgram/ml). NAPA decreased blood pressure (p less than 0.005), increased corrected Q-T interval (p less than 0.01) and increased the atrial and ventricular effective refractory periods from 267 +/- 40 to 307 +/- 41 ms (p less than 0.01) and from 278 +/- 37 to 301 +/- 32.8 ms (p less than 0.05), respectively. NAPA did not significantly change sinus cycle length or sinus nodal recovery time, conduction intervals (A-H, H-V, P-R, QRS), atrioventricular nodal functional refractory period or nodal Wenckebach cycle length. The patient receiving the largest dose experienced mild nausea when the plasma concentration was above 35 microgram/ml. These data show that the electrophysiology of NAPA in human beings is different from that reported for procainamide. At the plasma concentrations studied NAPA increases atrial and ventricular refractory periods without increasing cardiac conduction times     

Electrophysiologic evaluation of encainide with use of monophasic action potential recording

The electrophysiologic effects of encainide in the intact dog heart were evaluated with the use of monophasic action potential and His bundle recordings. Eight mongrel dogs were given 2.7 mg/kg body weight of encainide in two intravenous infusions. Plasma concentration, blood pressure, surface electrocardiogram, atrial and His bundle electrograms, right atrial and ventricular monophasic action potentials and the right atrial and ventricular effective and functional refractory periods were recorded before and 15 to 45 minutes after each infusion. Basic cycle length and A-H, H-V, QRS and Q-T_C intervals were significantly prolonged after administration of the drug. The refractory periods and the monophasic action potential durations were significantly increased in both the atrium and the ventricle although the increases were more pronounced in the atrium. It is concluded that encainide is a class I antiarrhythmic agent with properties very similar to those of quinidine.     

Electrophysiologic studies in the syndrome of short P-R interval, normal QRS complex

Eighteen subjects with a short P-R interval (<0.12 second) and normal QRS complex were studied by means of His bundle recordings and programmed atrial premature depolarizations. Eight subjects had a history of supraventricular tachycardia. During sinus rhythm, the A-H interval was less than or at the lower limits of normal values (45 to 80 msec), and the H-V interval was normal (30 to 50 msec). Atrial pacing at rates of up to 160/min produced 3 types of responses. Thirteen subjects showed a progressive increase in A-H interval similar to that of normal subjects but to a lesser degree. Three subjects showed an initial increase at low pacing rates, followed by a plateau response and further increase at higher rates. Two subjects showed no significant increase in the A-H interval. In 6 of 8 subjects with supraventricular tachycardia, atrial premature depolarizations produced atrial echo beats and sustained supraventricular tachycardia in 4, indicating atrioventricular (A-V) nodal reentry as the mechanism for the supraventricular tachycardia. In 10 subjects, refractory periods of the various components of the A-V conducting system were found to be similar to those of subjects with a normal P-R interval. The data suggest the following possible explanations for the short P-R interval: (1) total or partial bypass of the A-V node; (2) an anatomically small A-V node; (3) a short or rapidly conducting intranodal pathway; or (4) isorhythmic A-V dissociation.     

Paroxysmal tachycardia with atrioventricular dissociation in a patient with a variant of pre-excitation syndrome

We report a patient with a variant of the pre-excitation syndrome who has paroxysmal tachycardia with a pattern of left bundle branch block and ventriculo-atrial dissociation. The tachycardia is precipitated by exercise, reproduced by atrial pacing and terminated with lidocaine. Between attacks the electrocardiogram revealed prominent R waves in right precordial leads and the vectorcardiogram displayed anterior displacement of the mean QRS vector, but neither was diagnostic of pre-excitation. The resting P-R interval (140 msec) and A-H interval (60 msec) were within normal limits, but the H-V interval (30 msec) was at or slightly below normal limits. Increasing heart rate from 80 to 150/min with atrial pacing increased A-H from 70 to 160 msec, but did not change the H-V interval. With pacing at 160/min, A-H lengthened progressively from 160 to 190 msec, but A-V remained constant at the critical limit of 190 msec. Accordingly, the H-V interval decreased until the His spike disappeared into the QRS or did not occur because of A-V block. At this point, the QRS complex changed to that seen during spontaneous tachycardia. Pacing was stopped, but tachycardia continued at 160/min and ventriculoatrial dissociation appeared. Lidocaine promptly restored sinus rhythm. We speculate that the patient has anomalous conduction between the lower segment of the A-V node and the ventricular septum (Mahaim fibers) and a reciprocating tachycardia which results from antegrade conduction down the anomalous pathway and retrograde conduction up the His-Purkinje system and lower A-V node. Ventriculo-atrial Wenckebach during the tachycardia excludes participation of atria and upper part of the A-V node in the re-entrant tachycardia. This variant of pre-excitation syndrome could easily be mistaken for “true ventricular tachycardia” and serious heart disease.     

Electrophysiologic effects of anterior septal arterial occlusion

The effect of reduction in anterior septal arterial flow on the conduction system was studied in seven anesthetized dogs. After 2 hours of occlusion P-Q, A-H and H-V intervals as well as atrioventricular nodal effective and functional refractory periods were significantly prolonged, sinoatrial conduction time was prolonged and the heart rate was decreased. The duration of the His bundle electrogram was significantly prolonged and the configuration altered. However, QRS duration did not prolong significantly. Fifteen minutes after reperfusion, A-H interval, duration of the His bundle electrogram, effective refractory period and functional refractory period returned toward control values. However, the H-V and QRS intervals as well as sinoatrial conduction time were unchanged after reperfusion. Thus, reduction of anterior septal arterial flow influences not only the distal but also the proximal portion of the conduction system; the most vulnerable part is probably the His bundle. The distal portion of the conduction system is directly influenced by ischemia itself, whereas the proximal portion is influenced through other mechanisms induced by reduction of anterior septal arterial flow.     

Electrophysiologic findings in patients with idiopathic hypertrophic subaortic stenosis

Thirteen patients with catheterization-proved idiopathic hypertrophic subaortic stenosis underwent intracardiac electrophysiologic study. There was a large incidence of arrhythmias and a strikingly large incidence of conduction system abnormalities among these patients. The P-A and A-H intervals were normal in all patients. Atrial pacing resulted in Mobitz type 1 block proximal to the His bundle at an abnormal rate (less than 140/min) in 2 of 12 patients (17 percent). H-V intervals were prolonged (greater than 50 msec) in 10 of 12 patients (83 percent) and were greater than 60 msec in 7 patients (58 percent). The atrial effective refractory period was prolonged in 3 of 12 patients and was markedly prolonged in 1 of them. Effective refractory period of the atrioventricular (A-V) node, determined in five patients, was prolonged in three. Dual responses of the A-V node to atrial extrastimuli were found in seven patients. Dual A-V nodal repsonses were evoked with propranolol in three patients and persisted in the other four patients with dual responses despite propranolol administration.     

Familial occurrence of sinus bradycardia, short PR interval, intraventricular conduction defects, recurrent supraventricular tachycardia, and cardiomegaly.

Four members of a family presenting with sinus bradycardia, a short P-R interval, intraventricular conduction defects, recurrent supraventricular tachycardia (SVT), syncope, and cardiomegaly had His bundle studies and were found to have markedly shortened A-H intervals (30 to 55 msec.) with normal H-V times (35 to 50 msec.). Right atrial pacing at rates as high as 170 to 215 per minute failed to increase the A-H or H-V intervals significantly. The data are compatible with the presence of an A-V nodal bypass tract (James bundle) or even complete absence of an A-V node. Ventricular pacing and spontaneous ventricular premature beats resulted in a short ventriculoatrial conduction time (110 msec.) suggesting that if A-V nodal bypass tracts exist, they are utilized in an antegrade and retrograde fashion. None of the features of WPW syndrome was present. The mechanism of syncope in the mother and daughter was intermittent third-degree heart block. Both went on to develop permanent complete heart block despite electrophysiologic studies demonstrating 1:1 A-V conduction at extremely rapid atrial pacing rates and both required implantation of permanent pacemakers. The mechanism of syncope in the two brothers was possibly marked sinus bradycardia, but transient complete heart block has not been ruled out. Permanent pacemaker therapy was recommended for both. The nature of the cardiomegaly, which was mild in three patients, is not known. Although not well documented, several maternal relatives have had enlarged hearts, SVT, complete heart block, and syncope.     

Time dependent changes in the functional properties of the atrioventricular conduction system in man.

Time dependent changes in the electrophysiological properties of the atrioventricular conducting system (AVCS) were determined at two or more cycle lengths (CL) in 22 patients using bundle of His (H) electrograms, incremental atrial pacing and atrial extrastimulus method. The atrioventricular (A-H interval) and intraventricular (H-V interval) conduction times and refractory periods (RP) of the atrium, the A-V node (AVN) and His-Purkinje system (HPS) were measured during the control period, and repeat measurements were made after a 30 minute interval in eight patients (group A), after a 60 minute interval in nine (group B) and after 30 and 60 minute intervals in five (group C). No statistically significant changes from control values were seen after 30 and 60 minute intervals in any group in sinus rate, A-V nodal conduction time and the onset of A-V nodal Wenckebach block. H-V intervals were identical to the control values in all groups. Insignificant changes from control values occurred in RP of the atrium and HPS. Only the functional refractory period (FRP) of the AVN showed a statistically significant decrease from control values in groups B and C. This decrease could be explained by changes in autonomic tone. These observations in general confirm the reproducibility of electrophysiological properties of AVCS within one hour, and further support the validity of the techniques utilized in this and previously reported studies in the evaluation of cardioactive drugs.     

Ventricular activity during atrial fibrillation. Studies with His bundle electrography.

His bundle electrograms were recorded in 12 patients with atrial fibrillation. In all cases but one, the dominant rhythm was atrial fibrillation. In 1 case the dominant rhythm was fascicular tachycardia due probably to digitalis overdosage. However ventricular, fascicular and junctional beats could be often recognized on His bundle tracings, even when QRS configuration was similar to supraventricular conducted beats due to atrial fibrillation. In the patients in whom sinus rhythm occurred, the H-V interval was unchanged. Although it is admitted that during atrial fibrillation the zone of concealment of A-V conduction is in the A-V nodal area, concealed penetration of atrial impulses in the fascicular system may be encountered in patients not treated with digitalis.     

Effect of intravenous amiodarone in patients with intraventricular conduction disorders

Using His bundle recordings and stimulation techniques, theelectrical effects of amiodarone (5 mg/kg intravenously) wereassessed in 12 patients aged 34–80 years (mean 65) exhibitingin sinus rhythm, intraventricular conduction disturbances. Bundlebranch block was present in 10 patients: left bundle branchblock in three patients, right bundle branch block in three,bilateral bundle branch block in four. All the patients hada long H-V interval (65–80 ms; mean 71). As has been previouslyreported, amiodarone slowed the sinus rate, prolonged the QTinterval, increased the atrial effective refractory period anddepressed A-V nodal conduction. Despite the presence of advancedconduction disturbances within the His-Purkinje system, amiodaronedid not alter the H-V interval in 11 patients and increasedit in one by only 5 ms. Thus, clinically, the use of amiodaronein patients with bundle branch block should be safe.     

Atrioventricular nodal gap conduction as a manifestation of dual nodal pathways

Electrophysiologic studies were performed in a 76 year old patient for evaluation of sinus bradycardia. Atrial extrastimuli were induced during sinus rhythm at progressively decreasing coupling (A1-A2) intervals. At an A1-A2 interval of 420 msec, right bundle branch block developed, and at 370 msec conduction failed below the His bundle. When the interval was reduced to 320 msec, conduction resumed with a normal QRS pattern with an abrupt increase in A-H intervals from 165 to 305 msec. These findings are interpreted as type I or atrioventricular (A-V) nodal gap conduction physiologically related to conversion from a rapid to a slow A-V nodal conduction mode.     

Effect of glucagon on cardiac conduction in man

His bundle electrograms were obtained in 26 patients before and after intravenous administration of glucagon (50 μg/kg). The group consisted of 4 patients with normal conduction and 22 patients with conduction disease. The P-A interval, measured in all patients, was 35 ± 1.4 msec (mean ± standard error of the mean) before and 30 ± 1.5 msec after infusion of glucagon (P < 0.001). The mean A-H interval during sinus rhythm in all patients and during pacing at 100/min in 21 patients was, respectively, 97 ± 6.0 msec and 114 ± 6.4 msec before, and 96 ± 6.0 msec and 114 ± 6.6 msec after infusion of glucagon (not significant). The mean H-V interval in 25 patients was 48 ± 2.6 msec before and 49 ± 2.0 msec after infusion of glucagon (not significant). The mean sinus rate and sinus recovery times were, respectively, 73 ± 3.0 beats/min and 1,025 ± 42.0 msec before and 81 ± 3.0 beats/min and 919 ± 27.0 msec after infusion of glucagon (P < 0.001 and < 0.01). Functional and effective refractory periods were measured (In milliseconds) with use of the atrial extrastimulus technique. The mean atrial functional and effective refractory periods (21 patients) were, respectively, 273 ± 11.6 and 252 ± 12.0 before and 256 ± 10.0 and 238 ± 9.6 after infusion of glucagon (P < 0.001 and < 0.01). Mean atrloventricular (A-V) nodal functional refractory period (22 patients) and effective refractory period (15 patients) were 465 ± 22.0 and 404 ± 33.0 before and 457 ± 23.0 and 395 ± 32.0 after the infusion (not significant). The mean effective refractory period of the His-Purkinje system (2 patients) was 440 ± 45.0 before and 425 ± 55.0 after infusion of glucagon (not significant).In summary, glucagon increased sinus nodal automaticity, as manifested by an increase in sinus rate and decrease of sinus nodal recovery time, and improved intraatrial conduction as manifested by a reduction of the P-A interval and atrial functional and effective refractory periods. Glucagon had no effect on A-V nodal or intraventricular conduction.     

Electrophysiologic effects of pindolol on atrioventricular conduction in canine heart.

The effects of intravenous pindolol on the electrophysiologic properties of the atrioventricular conduction system was studied in intact dog, using His bundle electrogram and the extrastimulus method. Pindolol was administered intravenously in a dose range of 4 to 40 micrograms/Kg. The latter dosage of pindolol is above those used clinically. Significant effects of intravenous pindolol were observed on sinus cycle length, the A-V nodal conduction time, the ERP of the atrium, the ERP and FRP of the A-V node, and the ERP of the ventricle. Sinus cycle length was prolonged during sinus rhythm. Intraatrial conduction time was not altered by pindolol, while the ERP of the atrium was slightly increased. The A-H interval was generally prolonged by pindolol without Wenckebach type A-V block, but the H-V interval was unchanged. Both ERP and FRP of the A-V node was prolonged. The ERP and RRP of the His-Purkinje system were not statistically evaluated, because no block within the His-Purkinje system were not statistically evaluated, because no block with the His-Purkinje system or prolongation of H-V interval was produced and only a few QRS complexes by extrastimulus showed aberrant configration in the intact canine heart. In addition, pindolol prolonged the ERP of the ventricle.     

Exposure of concealed right bundle branch block in Wolff-Parkinson-White type B by pacing from the vicinity of the A-V node.

In two infants with Wolff-Parkinson-White type B, right bundle branch block was concealed during sinus rhythm and pacing from close to the atrial entrance of the right-sided accessory pathway. However, pacing from the vicinity of the A-V node, the A-V node itself, and the His bundle exposed the right bundle branch block by producing exclusive ventricular activation through the normal, A-V nodal His-Purkinje pathway. In addition, pacing from close to the A-V node also resulted in fusion beats characterized by absence of delta waves with (pseudo) normal QRS complexes and short H-V intervals. False patterns of tachycardia-dependent and bradycardia-dependent block in the accessory pathway also occurred. These dynamic phenomena were attributed to the (peri-A-V nodal) pacing-related, relatively early arrival of excitation at the ventricles through the normal pathways coexisting with delayed arrival of excitation via the accessory pathway. The latter in turn was due to the longer intra-atrial conduction time from paced (peri-A-V nodal) site to atrial entrance of the accessory pathway.     

Evidence suggesting dual A-V nodal pathways in patients without supraventricular tachycardias.

Electrophysiologic evidence for dual pathways of conduction through the A-V node is presented in three patients without history of supraventricular tachycardia. In case 1, abrupt spontaneous changes in the PR interval from 0.17 to 0.42 second were seen. His bundle electrographic studies showed two sets of A-H intervals during sinus rhythm and at several atrial pacing rates, although at rates over 100 per minute only the slow pathway conducted. Using the extrastimulus method, different refractory periods for the fast and slow pathways were documented. Cases 2 and 3 underwent His bundle electrography studies to evaluate intraventricular conduction defects. During atrial pacing studies abrupt changes in the A-H interval, from 220 to 470 msec and from 220 to 370 msec, were observed on increasing the pacing rate from 90 to 95 per minute in case 2 and from 120 to 130 per minute in case 3. In these two patients, dual A-V nodal pathways were suggested by the sudden changes in the A-H -interval at critical pacing rates. These findings indicate that evidence suggesting dual pathways of conduction through the A-V node may not be an uncommon finding and may be present without the manifestation of recurrent supraventricular tachycardias.     

Does A-H interval accurately represent intranodal conduction time during ectopic rhythms?

In order to determine whether the A-H interval of the His bundle electrogram accurately represents the AV nodal conduction time under various conditions, His bundle and coronary sinus electrograms were recorded in isolated perfused rabbit hearts, with atrial stimulation from eight different sites. The S-A (stimulus to the A wave) interval was significantly longer, whereas the A-H interval was shorter on stimulations from the coronary sinus and the left atrium than on sinus nodal stimulation. Stimulations from the fossa ovalis and right atrial appendage did not significantly alter the A-H interval. The effective and functional refractory periods of the AV node were almost identical with stimulations from the sinus node, low right atrial appendage, low left atrial appendage or the ostium of coronary sinus. Mapping of the excitation process with microelectrodes revealed that the activation times in low interatrial septal fibers bordering the His bundle [abbreviated as AP(III)] was closest to the A wave as compared with the activation in the ostium of the coronary sinus [AP(I)] or near the AN region [AP(II)] on stimulation from both sinus nodal and coronary sinus regions. On sinus nodal stimulation, AP(III) preceded AP(I) and AP(II) but lagged behind the A wave by 6 msec, whereas AP(III) preceded the A wave by 5 msec on coronary sinus stimulation. Thus, the A-H interval may not always accurately represent the intranodal conduction time, as relative timing of atrial activation responsible for the A wave and that of invasion of the AV node by the atrial wavefront can be grossly altered by different atrial excitation patterns.     

Pseudo A-V block associated with A-H and H-V conduction defects

His bundle electrograms were recorded in a patient with tertiary syphilis whose ECG's showed right bundle branch block, junctional premature systoles, and episodes suggesting both Mobitz Type I and II second degree A-V block. Junctional premature depolarizations were found to cause: (1) ventricular systole, (2) retrograde atrial depolarizations with atrial fusion, and (3) nonconducted P waves of normal contour (pseudo A-V block). Nonconducted nonpremature P waves were also noted to occur secondary to both A-H and H-V forms of second degree A-V block in the absence of junctional premature activity.The presence of an H-V conduction defect may cause antegrade block of junctional premature depolarizations and enhance their expression as pseudo A-V block. This term should, therefore, not be meant to imply A-H and H-V conduction.     

AV nodal reentrant tachycardia with Mahaim fiber conduction

Paroxysmal tachycardia with widened QRS complexes was found in a 46-year-old woman. In sinus rhythm, the patient had electrocardiographic evidence of type B preexcitation with a left bundle branch block pattern. The resting PR interval (160 msec) and A-H interval (100 msec) were within normal limits, but the H-V interval (10 msec) was abnormally short. Programmed atrial extrastimuli at progressively shorter coupling intervals resulted in sudden prolongation of the A-H interval from 120 msec to 250 msec, and the His bundle activities became incorporated just after initiation of the QRS complexes. The QRS morphology was changed but the change was minimal, and atrial echo beats or sustained tachycardia with wide and preexcited QRS complexes were elicited. It is postulated that the site of reentry is within the AV node with preexcitation occurring as the result of conduction in an anomalous nodoventricular pathway.